ISOQUINOLINE COMPOUNDS AND THEIR USE IN TREATING AhR IMBALANCE

ABSTRACT

The present invention is directed to novel compounds of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof. Pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, are also described. The invention is also directed to use of the compounds of Formula (I) for treating a condition in a mammal associated with AhR imbalance, such as an inflammatory disease or disorder.

CROSS REFERENCE TO RELATED APPLICATION

The present application is a Divisional of U.S. application Ser. No.17/587,812, entitled “ISOQUINOLINE COMPOUNDS AND THEIR USE IN TREATINGAhR IMBALANCE”, filed Jan. 28, 2022, which is a Divisional of U.S.application Ser. No. 17/332,805, entitled “ISOQUINOLINE COMPOUNDS ANDTHEIR USE IN TREATING AhR IMBALANCE”, filed May 27, 2021, now U.S. Pat.No. 11,267,788, which claims benefit of and priority to U.S. ProvisionalNo. 63/052,561 entitled “ISOQUINOLINE COMPOUNDS AND THEIR USE INTREATING AhR IMBALANCE,” filed Jul. 16, 2020; and U.S. Provisional No.63/052,574 entitled “ISOQUINOLINE COMPOUNDS AND THEIR USE IN TREATINGAhR IMBALANCE,” filed Jul. 16, 2020; the contents of which are herebyincorporated by reference in their entirety.

SUMMARY OF THE INVENTION

Various embodiments provide compounds and compositions, and methods forthe treatment and prevention of conditions associated with AhRimbalance, AhR mediated diseases and inflammatory disorders comprisingadministering such compounds and compositions. Compounds describedherein bind and activates the Aryl hydrocarbon Receptor (AhR), providinga novel class of anti-inflammatory compounds with AhR-dependent cytokinemodulation useful for the treatment of inflammatory disease states.

Some embodiments disclosed herein are directed to a compound of Formula(I) or a salt, solvate or hydrate thereof

wherein

each of R¹ and R² is independently selected from the group consisting ofOH, OR⁷, and H, provided that at least one of R¹ and R² is —OH or —OR⁷;

R⁷ is independently selected from the group consisting of optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,optionally substituted aryl, aryl C₁₋₆ alkyl and acyl;

R³ is selected from the group consisting of optionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted aryl, optionally substituted aryl C₁₋₆alkyl, optionally substituted C₃₋₆ cycloalkyl, optionally substitutedC₄₋₆ cycloalkenyl, halo, cyano, —C(O)OR⁸, —NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰,—C(O)R¹¹, —OR¹², —S(O)_(n) R¹³, and optionally substituted heterocyclyl;

R⁸ is selected from the group consisting of H, optionally substitutedC₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl, optionallysubstituted aryl, and optionally substituted aryl C₁₋₆ alkyl;

each of R⁹ and R¹⁰ is independently selected from the group consistingof H, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substituted aryl, and optionally substituted arylC₁₋₆ alkyl, or alternatively, R⁹ and R¹⁰ together with the nitrogen atomto which they are attached form a 5-7 membered cyclic saturated orunsaturated ring;

R¹¹ is independently selected from the group consisting of H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted aryl, optionallysubstituted aryl C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,—NR⁹R¹⁰ , and —OR¹²;

each of R¹² and R¹³ is independently selected from the group consistingof H, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted aryl C₁₋₆ alkyl, and optionally substituted C₃₋₆ cycloalkyl;

R⁶ is selected from the group consisting of H, halo, hydroxyl, alkoxy,optionally substituted C₁₋₆ alkyl, halogenated alkyl; optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, andoptionally substituted aryl C₁₋₆ alkyl;

n is an integer having a value of 0, 1 or 2;

s is an integer having a value of 0, 1 or 2;

t is an integer having a value of 0 to 6;

R⁵ is selected from the group consisting of H, halo, optionallysubstituted C₁₋₆ alkyl, —C(O)OR¹⁴, —C(O)NR¹⁵R¹⁶, aryl and —C₁₋₆alkylaryl;

R¹⁴ is selected from the group consisting of H, optionally substitutedC₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl, optionallysubstituted aryl, and optionally substituted aryl C₁₋₆ alkyl;

each of R¹⁵ and R¹⁶ is independently selected from the group consistingof H, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substituted aryl, optionally substituted arylC₁₋₆ alkyl, and optionally substituted C₃₋₆ cycloalkyl; alternativelyR¹⁵ and R¹⁶ together with the nitrogen to which they are attached, forma 5-7 membered cyclic saturated or unsaturated ring;

R⁴ is selected from the group consisting of H, halo, cyano, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted aryl, optionallysubstituted aryl C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,—(CR¹⁸R¹⁹)_(t)COOR⁸, —(CR¹⁸R¹⁹)_(t)OC(O)R⁸, —(CR¹⁸R¹⁹)_(t)NR⁹R¹⁰,—(CR¹⁸R¹⁹)_(t)C(O)NR⁹R¹⁰, —(CR¹⁸R¹⁹)_(t)NR⁹C(O)R⁸,—(CR¹⁸R¹⁹)_(t)S(O)₂NR⁹R¹⁰, —(CR¹⁸R¹⁹)_(t)COR¹¹, —(CR¹⁸R¹⁹)_(t)CH(O),—(CR¹⁸R¹⁹)_(t)OR¹², —(CR¹⁸R¹⁹)_(t)S(O)_(s)R¹³, optionally substitutedheterocyclic, and optionally substituted heterocyclic C₁₋₆ alkyl; and

each of R¹⁸ and R¹⁹ is independently selected from the group consistingof H, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substituted aryl, and optionally substituted arylC₁₋₆ alkyl.

Some embodiments are directed to a compound selected from the groupconsisting of:

or a salt, solvate or hydrate thereof.

Some embodiments are directed to a compound of the formula

Some embodiments are directed to a compound of the formula

or a pharmaceutically acceptable salt, solvate of hydrate thereof.

Some embodiments are directed to2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt solvate of hydrate thereof.

Some embodiments describe a compound of Formula (II) or a salt solvateor hydrate thereof:

wherein

each R¹ and R² is independently selected from the group consisting ofOH, OR⁷, and H, provided that at least one of R¹ and R² is OH or OR⁷;

R⁷ is independently selected from the group consisting of optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,optionally substituted aryl, optionally substituted aryl C₁₋₆ alkyl, andacyl;

R³ is selected from optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted aryl, optionally substituted aryl C₁₋₆ alkyl,optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₄₋₆cycloalkenyl, halo, cyano, —C(O)OR⁸, —NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰, —C(O)R¹¹,—OR¹², —S(O)_(n)R¹³ and optionally substituted heterocyclic ring;

n is an integer having a value of 0, 1 or 2;

R⁶ is H;

R⁸ is selected from the group consisting of H, optionally substitutedC₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl, optionallysubstituted aryl, and optionally substituted aryl C₁₋₆ alkyl;

each of R⁹ and R¹⁰ is independently selected from the group consistingof H, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substituted aryl, and optionally substituted arylC₁₋₆ alkyl; alternatively, R⁹ and R¹⁰ together with the nitrogen atom towhich they are attached, form a 5-7 membered cyclic saturated orunsaturated ring;

R¹¹ is selected from the group consisting of H, optionally substitutedC₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substitutedC₂₋₆ alkynyl, optionally substituted aryl, optionally substituted arylC₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl; —NR⁹R¹⁰ , and —OR¹²;

each of R¹² and R¹³ is independently is selected from the groupconsisting of H, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted aryl C₁₋₆ alkyl, and optionally substituted C₃₋₆cycloalkyl; and

R⁶ is selected from the group consisting of halo, hydroxyl, alkoxy,optionally substituted C₁₋₆ alkyl, halogenated alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, andoptionally substituted aryl C₁₋₆ alkyl.

Some embodiments herein describe a pharmaceutical compositioncomprising: a compound according to any embodiment described herein, ora pharmaceutically acceptable salt, solvate or hydrate thereof; and apharmaceutically acceptable carrier or diluent.

Some embodiments describe a method of treating or preventing a conditionin a mammal associated with AhR imbalance, comprising administering tothe mammal a therapeutically effective amount of any compound orpharmaceutical composition described herein.

Some embodiments describe a method of treating or preventing aninflammatory disorder in a subject, comprising administering to thesubject a therapeutically effective amount of any compound orpharmaceutical composition described herein. In some embodiments theinflammatory disorder is selected from the group consisting ofpsoriasis, atopic dermatitis, vitiligo, acne, neovascular (dry) AMD,neovascular (wet) AMD, uveitis or other inflammatory eye conditions,radiation dermatitis, COPD, asthma, multiple sclerosis (MS), andinflammatory bowel disease. In some embodiments the inflammatorydisorder is psoriasis or atopic dermatitis. In some embodiments thecompound or a pharmaceutical composition described herein isadministered topically.

Some embodiments describe a method of treating or preventing psoriasisor atopic dermatitis in a subject in need thereof, comprisingadministering to the subject an effective amount of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe a process for preparing a compound of Formula8

-   -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof, comprising:    -   a) preparing a compound of Formula 5

-   -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof, comprising        -   1) alkylating 2,6-dihydroxyacetophenone or a            pharmaceutically acceptable salt, solvate or hydrate            thereof, to form a compound of Formula 2

-   -    or a pharmaceutically acceptable salt, solvate or hydrate        thereof;        -   2) treating the ketone of Formula 2 or a pharmaceutically            acceptable salt, solvate or hydrate thereof with a Grignard            reagent, followed by elimination of water under acidic            conditions to form a compound of Formula 3

-   -    or a pharmaceutically acceptable salt, solvate or hydrate        thereof;        -   3) hydrogenating the compound of Formula 3 or a            pharmaceutically acceptable salt, solvate or hydrate thereof            to form a compound of Formula 4

-   -    or a pharmaceutically acceptable salt, solvate or hydrate        thereof; and        -   4) borylating the compound of Formula 4 or a            pharmaceutically acceptable salt, solvate or hydrate thereof            to form the compound of Formula 5        -   or a pharmaceutically acceptable salt, solvate or hydrate            thereof;    -   b) preparing a compound of Formula 6

-   -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof comprising treating isoquinoline-3-ol with a triflating        agent; and    -   c) coupling the compound of Formula 6 or a pharmaceutically        acceptable salt, solvate or hydrate thereof with the compound of        Formula 5 or a pharmaceutically acceptable salt, solvate or        hydrate thereof to form a compound of Formula 7

-   -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof; and    -   d) demethylating the compound of Formula 7 to form the compound        of Formula 8. or a pharmaceutically acceptable salt, solvate or        hydrate thereof; wherein steps a and b can be done in either        order or simultaneously in different reaction vessels.

DESCRIPTION OF THE DRAWINGS

FIGS. 1A to 1U show the BioMAP profile of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol compared to tapinarofand F1CZ. FIGS. 1A to 1G shows the BioMAP profile of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol alone at concentrationsof 1.0 μM, 0.33 μM, 0.11 μM, and 0.037 μM, FIGS. 1H to 1N shows theBioMAP profile of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol at 1μM (light gray) overlaid with FICZ (330 nM; dark gray), and FIGS. 1O to1U shows the BioMAP profile of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol at 1 μM (light gray)overlaid with tapinarof (1 μM; dark gray). The shaded grey arearepresents normal variation. Common analytes outside normal variationare annotated.

FIGS. 2A to 2C show the effect of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol on IL-17A proteinsecretion in primary human peripheral blood CD4+ T-cells and cellviability in T-cells and keratinocytes. FIG. 2A shows suppression ofIL-17A in human peripheral blood CD4+ T-cells by2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (triangle) andtapinarof (circle) in a dose dependent manner under Th17 polarizingconditions. Points represent percent maximum expression of proteincompared to Th17 from six combined donors; 3 biological replicates pertreatment. Error bars represent standard error of mean. FIG. 2B showscell viability in human peripheral blood CD4+ T-cells under Th17polarizing conditions and increasing concentrations of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (diamond) and tapinarof(circle) over 5 days. Data are mean±standard error from 3 to 9experimental data points. FIG. 2C shows cell viability in human primarykeratinocytes. Cell viability was quantitated after treatment withincreasing concentrations of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (triangle) andtapinarof (circle) for two days. Error bars represent mean±standarderror of 10-15 biological replicates.

FIGS. 3A-3B show target engagement of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol induces AhR targetgene, CYP1A1, and reduces IL-17A expression in ex vivo human skin. Skinsamples from healthy donors placed in a liquid/air interface culturesystem and were pre-treated with or without 1 or 10 μM of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (white) or GSK3038548A(grey) for 24 hours then cultured under Th17 polarizing conditions foran additional 24 hours. FIG. 3A shows the relative expression of CYP1A1mRNA transcripts after 24 hours using qRT-PCR. FIG. 3B shows relativeexpression of IL-17A mRNA transcripts after 24 hours using qRT-PCR. Dataare represented as the mean from 3 or 4 biological replicates±standarderror. Student's t-test was used to determine statistical significance,*p<0.05.

FIG. 4 shows topical target engagement of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in cream formulation 1and gel formulation 1 at different concentrations. Skin samples fromhealthy donors placed in a liquid/air interface culture system weretreated with or without 10 μM2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol or 1 μM FICZ in themedia or topically applied at the indicated concentrations informulations for 24 hours. Relative expression of CYP1A1 mRNAtranscripts is reported as plots of the mean±SEM of 4 biologicalreplicates from 4 individual donors.

FIGS. 5A to 5F show the effects of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol on clinical score andepidermal thickness in the imiquimod mouse model of psoriasis.2-Isopropyl- 5-(isoquinolin-3-yl)benzene-1,3-diol was applied for 3 daysprior to IMQ treatment. Then, IMQ and2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in 60% ethanolictopical solution was applied to the shaved back sequentially (first IMQand then 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, 1-2 hrslater), for either 4 days at 0.3% (FIGS. 5A to 5B) or 9 days at 0.3% and0.1% (FIGS. 5C to 5D). In FIG. 5A plot the diamond represents vehicle(60% EtOH 40% water)+vanicream; the square represents vehicle+imiquimod(5%); the X represents 0.3%2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (60% EtOH 40%water)+imiquimod (5%). The other lines have no relevance to the presentapplication and are thus not identified. In FIG. 5B the epidermalthickness was measured on histology sections of back skin taken on thelast day of treatment. The triangle bar represents the vehicle (60% EtOH40% water)+vanicream; the oval bar represents vehicle+imiquimod (5%);the solid bar represents 0.3%2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (60% EtOH 40%water)+imiquimod (5%). In FIG. 5C plot the diamond represents vehicle(60% EtOH 40% water)+vanicream; the square represents vehicle+imiquimod(5%); the X represents 0.1%2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (60% EtOH 40%water)+imiquimod (5%) and the circle represents 0.3%2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (60% EtOH 40%water)+imiquimod (5%). In FIG. 5D the the epidermal thickness wasmeasured on histology sections of back skin taken on the last day oftreatment. The triangle bar represents the vehicle (60% EtOH 40%water)+vanicream; the oval bar represents vehicle+imiquimod (5%); thesquare bar represents 0.1%2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (60% EtOH 40%water)+imiquimod (5%); and the solid bar represents 0.3%2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (60% EtOH 40%water)+imiquimod (5%). In FIG. 5E, a second 9-day IMQ study wasperformed using 0.1% cream formulation 1 (square), 0.5% creamformulation 1 (X), and 1% cream formulation 1 (star). 0% creamformulation 1+vanicream is represented by a diamond and 0% creamformulation 1+imiquimod is respresented by a circle. In FIG. 5F the theepidermal thickness was measured on histology sections of back skintaken on the last day of treatment. The triangle bar represents thevehicle (0% cream formulation 1)+vanicream; the oval bar representsvehicle+imiquimod (5%); the square bar represents 0.1% cream formulation1+imiquimod (5%); the solid bar represents 0.5% 2 cream formulation1+imiquimod (5%) and the star bar represents 1% cream formulation1+imiquimod.

FIGS. 6A to 6E show the effect of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol on dermal and epidermalthickness in the DFNB mouse model. FIG. 6A shows a schematic ofexperimental design. Mice were sensitized to DNFB on day 1 andchallenged with DNFB every 2-3 days starting 5 days later. Topicalformulations of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol wereapplied daily beginning at day 5. FIG. 6B shows measures of epidermalthickness and FIG. 6C shows measures of dermal thickness in response totopical application of 1%2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol or 0.3%2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in 60% ethanolicsolutions (60% EtOH, 40% water) twice per day (BID). In FIGS. 6B and 6Cthe squared bar represents solvent (acetone/olive oil (4:1vol:vol)+vehicle (60% EtOH, 40% water), the diamond bar represents 0.15%DNFB (in acetone/olive oil (4:1 vol:vol)+vehicle (60% EtOH, 40% water),the star bar represents 0.15% DNFB (in acetone/olive oil (4:1vol:vol)+1% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol inethanolic solution (60% EtOH, 40% water), the solid bar represents 0.15%DNFB (in acetone/olive oil (4:1 vol:vol))+0.3%2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in ethanolic solution(60% EtOH, 40% water), and the hexagon bar represents 0.15% DNFB (inacetone/olive oil (4:1 vol:vol). FIG. 6D shows measures of epidermalthickness and FIG. 6E show dermal thickness in response to topicalapplication of 0% cream formulation 1 or 0% cream formulation 1 once perday. In FIGS. 6D and 6E the squared bar represents acetone/olive oil(4:1 vol:vol)+vehicle (60% EtOH, 40% water), the diamond bar represents0.15% DNFB (in acetone/olive oil (4:1 vol:vol))+vehicle (60% EtOH, 40%water), the circle bar represents 0.15% DNFB (in acetone/olive oil (4:1vol:vol)+0% cream formulation 1, the solid bar represents 0.15% DNFB (inacetone/olive oil (4:1 vol:vol))+0.3% cream formulation 1, and thehexagon bar represents 0.15% DNFB (in acetone/olive oil (4:1 vol:vol))and 0.05% clobetasol cream. One-way ANOVA was used to determinestatistical significance. *p<0.05, ***p<0.001, n=12 per treatment group.

FIG. 7 shows the amount of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in different 1%formulations delivered into the epidermis (square bar of bar set) anddermis (solid bar of bar set) 16 hours post-application. Bars representthe mean amount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol from15-18 replicates from 3 donors±SEM. Samples were analyzed by UPLC-MS/MSwith a LLOQ of 80 pg/mL.

FIG. 8 shows the cumulative amount of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (ng) in the receivingfluid over 16 hours post-application of different formulations. Thesquare represents 1% cream formulation 3; the circle represents 1% gelformulation 4; the asterisk represents 1% gel formulation 3; the singleperpendicular line represents 1% cream formulation 4; no symbol (line)represents 1% cream formulation 5; the triangle represents 1% creamformulation 6 the diamond represents 1% cream formulation 7; and thethick X represents 1% cream formulation 2. Lines represent thecumulative mean amount of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol from 15-18 replicatesfrom 3 donors±SEM. Samples were analyzed by UPLC-MS/MS with a LLOQ of 80pg/mL.

FIG. 9 shows the amount of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol delivered into thedermis 16 hours post application of different formulations. Barsrepresent the mean amount of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol from 13-16 replicatesfrom 3 donors ±SEM. Samples were analyzed by UPLC-MS/MS with an LLOQ of80 pg/mL*.

FIGS. 10A to 10B show the amount of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (m) delivered into theepidermis (square bar of each formulation) and dermis (solid bar of eachformulation) 16 hours post application for different gel formulations of2-isopropyl (isoquinolin-3-yl)benzene-1,3-diol. Bars represent the meanamount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol from 15-18replicates from 3 donors±SEM (FIG. 10A) and from 7-10 replicates from 1donor±SEM (FIG. 10B). Samples were analyzed by UPLC-MS/MS with an LLOQof 80 pg/mL.

FIG. 11 shows cumulative amount (ng) of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in the receiving fluidover 16 hours post application for different gel formulations. Thecumulative amount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diolfrom 15-18 replicates from 3 donors±SEM (N46822-2) is described for gelformulation 4 (diamond), gel formulation 1 (triangle) and gelformulation 2 (square). The cumulative amount of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol from 7-10 replicatesfrom 1 donor±is described for gel formulation 4 (asterisk) and gelformulation 3 (broad X). Samples were analyzed by UPLC-MS/MS with anLLOQ of 80 pg/mL.

FIGS. 12A to 12C show mean (SD) plasma concentration-time profiles of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol following a singleadministration in rat. In FIG. 12A,2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol is administeredintravenously (1 mg/kg). In FIG. 12B the solid square represents thesubcutaneous administration of 10 mg/kg of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in 30% Captisol; theopen square represents the subcutaneous administration of 25 mg/kg of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in 30% Captisol; thesolid triangle represents the subcutaneous administration of 10 mg/kg of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in 30% Cavitron and theopen triangle represents the subcutaneous administration of 25 mg/kg of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in 30% Cavitron. InFIG. 12C the solid circle represents the topical administration of 1%cream formulation 1 of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol(20 mg/kg) and the open square in FIG. 12C represents a topicalformulation of 1% gel formulation 1 of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (20 mg/kg).

FIGS. 13A to 13B show individual epidermis/upper dermis and dermisconcentration-time profiles of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol following a singletopical dose in minipigs. In FIG. 13A the solid line, open circle is theepidermis/upper dermis of minipig subject one treated with a 1% creamformulation 1 of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol; thedash line, open circle is the dermis of minipig subject one treated witha 1% cream formulation 1 of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol; the solid line, solidcircle is the epidermis/upper dermis of minipig subject two treated witha 1% cream formulation 1 of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol; and the dash line,solid circle is the dermis of minipig subject two treated with a 1%cream formulation 1 of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol.In FIG. 13B the solid line, solid circle is the epidermis/upper dermisof minipig subject one hundred one treated with a 1% gel formulation 1of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol; the dash line,solid circle is the dermis of minipig subject one hundred one treatedwith a 1% gel formulation 1 of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol; the solid line, opencircle is the epidermis/upper dermis of minipig subject one hundred twotreated with a 1% gel formulation 1 of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol; and the dash line,open circle is the dermis of minipig subject one hundred two treatedwith a 1% gel formulation 1 of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol.

FIGS. 14A-B show depth profiling and skin MALDI IMS at different timepoints following a single topical dose with: 1% cream formulation 1(FIG. 14A) and 1% gel formulation 1 (FIG. 14B) in minipig.

DETAILED DESCRIPTION OF THE INVENTION

The aryl hydrocarbon receptor (AhR), a member of the bHLH-PAS family oftranscription factors, is a cytosolic ligand-activated transcriptionfactor that senses diverse endogenous and exogenous molecules mediatingmultiple biological activities It is best known for mediating the toxiceffects of environmental contaminants such as TCDD (dioxin) and a rangeof other xenobiotic substances. Recent evidence points to AhR as ahighly-conserved pathway that can modulate inflammatory responses, thusthe AhR pathway could be an important target for treating inflammatorydiseases.

There is a wide expression of AhR in several cell types of the skin,including keratinocytes, fibroblasts, melanocytes, and skin immunecells. In keratinocytes, AhR signaling controls the expression ofepidermal differentiation genes, such as filaggrin, loricrin, andhornerin, thus promoting skin barrier formation. Additionally, it hasbeen shown that AhR plays a critical role as a regulator of both innateand adaptive immune responses by impacting the balance of Th17 and TregT cells. Th17-associated cytokines, including IL-17, contribute to theimmunopathogenesis of inflammatory skin diseases such as psoriasis.Therefore, attention has recently been drawn to AhR as a target for thetreatment or prevention of inflammatory skin diseases, concurrentlyhighlighting the need for better topical treatments.

Compounds such as those described herein, that bind and activate theAryl hydrocarbon Receptor (AhR), provide for a novel class ofanti-inflammatory compounds with AhR-dependent cytokine modulationuseful for the treatment of inflammatory disease states.

Thus, the beneficial effects of AhR activation provide for newtherapeutic interventions in the treatment of inflammatory diseasestates. The need exists for better topical treatment of skin diseases,and in particular chronic inflammatory skin diseases. Suitably, acompound which binds and activate the Aryl hydrocarbon Receptor (AhR) inmultiple cell types, including cells of the human skin, will provide anovel and useful treatment for inflammatory disease states. The presentinvention thus provides for a novel class of anti-inflammatory compoundswith AhR-dependent cytokine modulation for treatment thereof.

Definitions

It should be understood that the terms “a” and “an” as used herein referto “one or more” of the recited components. It will be clear to one ofordinary skill in the art that the use of the singular includes theplural unless specifically stated otherwise.

The term “about” means within an acceptable range for the particularparameter specified as determined by one of ordinary skill in the art,which will depend, in part, on how the value is measured or determined,i.e., the limitations of the measurement system. For example, “about”can mean a range of 10% of a given value. For example about 55% means45% to 55%.

As used herein, “acyl” mean an alkyl or aryl group bonded through acarbonyl group —C(O)—. For example, acyl includes a C₁₋₆ alkanoyl.Typical acyl groups include acetyl, benzoyl, and the like.

The terms “administering” and “administration” are used herein to meanany method which in sound medical practice delivers the compound orpharmaceutical composition thereof to a patient in such a manner as toprovide the desired therapeutic effect. In some embodiments the compoundis in a pharmaceutical emulsion composition.

As used herein, the term “alkoxy” refers to an —O-alkyl group containinga specified number of carbon atoms. For example, C₁₋₆ alkoxy meansalkoxy group containing at least 1, and at most 6, carbon atoms.Examples of “alkoxy”as used herein include, but are not limited to,methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy,2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy or hexyloxy.

As used herein, “alkyl” refers to a monovalent saturated hydrocarbonchain having the specified number of carbon member atoms. For example,C₁₋₆ alkyl refers to an alkyl group having from 1 to 6 carbon memberatoms. Alkyl groups may be straight or branched. Representative branchedalkyl groups have one, two, or three branches. Alkyl includes methyl,ethyl, propyl, (n-propyl and isopropyl), butyl (n-butyl, isobutyl,s-butyl, and t-butyl), and n-pentyl, and the like.

The term “alkylene” means a linker which is a straight or branchedcarbon chain having 1 to 6 carbon atoms and having two bonding sites.Examples of C₁₋₆ alkylene linker groups include but are not limited to—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—, and the like.

The term “and/or” as used herein covers both additively and alsoalternatively the individual elements of a list which are thus linked sothat these elements are to be understood as linked selectively with“and” or respectively with “or”. Furthermore, the terms used in thesingular of course also comprise the plural.

The term “applying” as used herein refers to any method which, in soundmedical or cosmetic practice, delivers a topical composition to thesubject in such a manner so as to provide a positive effect on adermatological disorder, condition, or appearance.

As used herein, the term “aryl” refers to substituted or unsubstitutedhydrocarbon aromatic rings such as phenyl, naphthyl and the like.

As used herein, the term “arylalkyl” or “araalkyl” refers to an arylring such as benzene or naphthalene and a connecting C₁₋₆ alkyl moiety,unless otherwise indicated, such as —(CH₂)_(n)phenyl wherein n is 1-6.

As used herein, the terms “compound(s) of the invention” or “compound(s)of this invention” mean a compound, as defined herein, in any form,i.e., any salt or non-salt form (e.g., as a free acid or base form, oras a salt, particularly a pharmaceutically acceptable salt thereof) andany physical form thereof (e.g., including non-solid forms (e.g., liquidor semi-solid forms), and solid forms (e.g., amorphous or crystallineforms, specific polymorphic forms, solvate forms, including hydrateforms (e.g., mono-, di- and hemi- hydrates)), and mixtures of variousforms.

Throughout the application, descriptions of various embodiments use“comprising” language, however in some specific instances, an embodimentcan alternatively be described using the language “consistingessentially of” or “consisting of”.

The term “dermatologically acceptable excipient or diluent” as usedherein refers to any inactive ingredient present in a composition foruse in a topical composition described herein.

“Effective amount”, “pharmaceutically effective amount” or“therapeutically effective amount” is used herein to refer to an amountof the active ingredient sufficient to have a therapeutic effect uponadministration, e.g. that amount which will cause an improvement orchange in the condition for which it is administered. Effective amountswill vary with the particular condition being treated, the severity ofthe condition, the duration of the treatment, the stage of advancementof the condition, the body surface area affected with the clinicalcondition (for topical administration), and the specific components ofthe composition. The amount is sufficient to treat a disorder, diseaseor condition or one or more of its symptoms and/or to prevent theoccurrence of the disease or disorder, and can be determined by standardclinical techniques. Appropriate amounts in any given instance will bereadily apparent to those skilled in the art or capable of determinationby routine experimentation. In some embodiments, compositions of theinvention are generally applied in a topical manner to the affectedarea, i.e. localized application to the skin region where the clinicalabnormality is manifest.

As used herein, the term “haloalkyl” or “halo substituted alkyl” refersto a straight or branched saturated hydrocarbon chain containing aspecified number of carbon atoms, substituted with halo atoms. Forexample, halo C₁₋₆ alkyl means a straight or branched alkyl groupcontaining at least 1, and at most 6, carbon atoms, substituted with 1to 3 halo atoms per carbon atom. Examples of “haloalkyl” as used hereininclude, but are not limited to, fluoromethyl, difluoromethyl, andtrifluoromethyl.

As used herein, the terms “halogen” and “halo” include fluorine,chlorine, bromine and iodine, and fluoro, chloro, bromo, and iodo,respectively.

As used herein, the terms “heteroaryl ring”, “heteroaryl moiety”, and“heteroaryl” mean a monocyclic five to seven membered unsaturatedhydrocarbon ring containing at least one heteroatom selected fromoxygen, nitrogen and sulfur. Examples of heteroaryl rings include, butare not limited to, furyl, pyranyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,oxathiadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and uracil. The terms“heteroaryl ring”, “heteroaryl moiety”, and “heteroaryl” as used herein,also refer to fused aromatic rings comprising at least one heteroatomselected from oxygen, nitrogen and sulfur. Each of the fused rings maycontain five or six ring atoms. Examples of fused aromatic ringsinclude, but are not limited to, indolyl, isoindolyl, indazolyl,indolizinyl, azaindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl,benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, cinnolinyl, purinyl, and phthalazinyl.

As used herein, the term “heteroarylalkyl” means a C₁₋₆ alkyl as definedabove, (unless otherwise defined) attached to a heteroaryl moiety asalso defined herein unless otherwise indicated.

As used herein, the term “heterocyclicalkyl” or “heterocyclylalkyl”means a C₁₋₆ alkyl as defined above, (unless otherwise defined) attachedto a heterocyclic moiety as also defined herein unless otherwiseindicated

As used herein, the term “heterocyclic” or “heterocyclyl” (on its own orin any combination, such as “heterocyclylalkyl”) is used herein to meana saturated or partially unsaturated 4 to 10 membered ring system inwhich one or more rings contain one or more heteroatoms selected fromthe group consisting of N, O, S, or S(O)q, wherein q is 0 or an integerhaving a value of 1 or 2. Examples include, but not limited to,tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl,tetrahydrothiophenyl (including oxidized versions of the sulfur moiety),pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl(including oxidized versions of the sulfur moiety), or imidazolidinyl.

As used herein in the in vitro skin penetration studies, the term“epidermis” includes the stratum corneum and tissue or layers down tothe basement membrane, as isolated by heat separation treatment.

As used herein in the in vitro skin penetration studies with ex vivohuman abdominal skin dermatomed at a thickness of 500 microns (+/−100microns) or 750 (+/−100 microns), the term “epidermis” is the top/superficial layer obtained after a washing/tape striping procedurefollowed by heat separation, and the term “dermis” is the underlyinglayer.

As used herein, the term “independently” means that where more than onesubstituent is selected from a number of possible substituents, thosesubstituents may be the same or different. That is, each substituent isseparately selected from the entire group of recited possiblesubstituents.

The terms “modulate” or “modulates” refer to an increase or decrease inthe amount, quality or effect of a particular activity.

As used herein, the term “oxo” represents a double-bonded oxygen moiety;for example, if attached directly to a carbon atom it forms a carbonylmoiety (C═O).

As used herein, the term “hydroxy” or “hydroxyl” is intended to mean theradical —OH.

As used herein, the term “sulfinyl” is used herein to mean the oxideS(O) of the corresponding sulfide, the term “thio” refers to thesulfide, and the term “sulfonyl” refers to the fully oxidized S(O)₂moiety.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s) thatoccur and event(s) that do not occur.

As used herein, “optionally substituted”, unless specifically definedherein shall mean the moiety may be optionally substituted one or moretimes, such as one to three times, independently with halo, e.g. fluoro,chloro, bromo or iodo; hydroxy; hydroxy substituted C₁₋₃ alkyl; C₁₋₃alkoxy, such as methoxy or ethoxy; halo substituted C₁₋₃ alkoxy;S(O)_(m)C₁₋₃ alkyl, such as methyl thio, methylsulfinyl or methylsulfonyl; NR²²R²³, wherein R²² and R²³ are independently selected from Hor C₁₋₃ alkyl or wherein R²² and R²³ together with the nitrogen to whichthey are attached form a 5 to 7 membered ring which optionally containsan additional heteroatom selected from O, N, or S; C₁₋₃ alkyl; C₃₋₇cycloalkyl, or C₃₋₇ cycloalkyl C₁₋₃ alkyl group, such as cyclopropylmethyl; halosubstituted C₁₋₃ alkyl, such CF₂CF₂H, or CF₃; optionallysubstituted aryl, such as phenyl or optionally substituted aryl C₁₋₃alkyl, such as benzyl or phenethyl, and wherein these aryl containingmoieties may also be substituted one to two times by halo; hydroxy;hydroxy substituted C₁₋₃ alkyl; C₁₋₃ alkoxy; S(O)_(m)C₁₋₃ alkyl; amino,mono and di-substituted C₁₋₃ alkylamino; C₁₋₃ alkyl, or CF₃. Inaddition, it will be appreciated by those skilled in the art that thecompounds of this invention, depending on further substitution, mayexist in other tautomeric forms. All tautomeric forms of the compoundsdescribed herein are intended to be encompassed within the scope of thepresent invention. It is to be understood that any reference to a namedcompound of this invention is intended to encompass all tautomers of thenamed compound and any mixtures of tautomers of the named compound.

As used herein, “patients” includes human patients, including adult,teens and children (e.g. pediatric patients). A pediatric patient caninclude teenagers under the age of 18. A child for purposes herein isunder the age of 12.

As used herein, “pharmaceutically acceptable” refers to those compounds,materials, compositions, and dosage forms which are, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhuman beings and animals without excessive toxicity, irritation, orother problem or complication, commensurate with a reasonablebenefit/risk ratio. The terms “pharmaceutically acceptable” and“dermatologically acceptable” mean approvable by a regulatory agency orlisted in a Pharmacopeia or other generally recognized guide for use inanimals, and more particularly in humans.

The term “pharmaceutically acceptable salt thereof” refers to salts thatare safe and effective for use in the patient and possess the desiredpharmaceutical activity. Salts encompassed within the termpharmaceutically acceptable salts refer to non-toxic salts of thecompounds of this invention. Such salts include compounds wherein theparent compound is modified by making acid or base salts thereof.

As used herein, the term “skin penetration” refers to the diffusion of acompound, preferably a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof through the stratum corneum and into theepidermis and/or dermis of the skin.

“Substantially free” of a specified component refers to a compositionwith less than about 1% by weight of the specified component. “Free” ofa specified component refers to a composition where the specifiedcomponent is absent.

As used herein, the term “substituted” in reference to a group indicatesthat one or more hydrogen atom attached to a member atom within thegroup is replaced with a substituent selected from the group of definedsubstituents. It should be understood that the term “substituted”includes the implicit provision that such substitution be in accordancewith the permitted valence of the substituted atom and the substituentand that the substitution results in a stable compound (i.e. one thatdoes not spontaneously undergo transformation such as by rearrangement,cyclization, or elimination and that is sufficiently robust to surviveisolation from a reaction mixture). When it is stated that a group maycontain one or more substituents, one or more (as appropriate) memberatoms within the group may be substituted. In addition, a single memberatom within the group may be substituted with more than one substituentas long as such substitution is in accordance with the permitted valenceof the atom. Suitable substituents are defined herein for eachsubstituted or optionally substituted group.

The term “topical” delivery or “topical” administration refers toapplication of a drug-containing formulation to the skin to directlytreat cutaneous disorders or the cutaneous manifestations of a diseasewith the intent of substantially directing the pharmacological effect ofthe drug to the surface of the skin or within the skin. The term“topical” delivery also includes dermal, inhaled and ocular/oticadministration. “Topical” administration also refers to application toand diffusion through the stratum corneum, including but not limited toapplication to psoriatic lesions and broken skin.

The term “treating” or “treatment” as used herein refers toadministration of a compound or agent to a subject who has a disorder oris at risk of developing the disorder with the purpose to cure,alleviate, relieve, remedy, delay the onset of, prevent, or amelioratethe disorder, the symptom of the disorder, the disease state secondaryto the disorder, or the predisposition toward the disorder. Treatmentneed not mean that the condition or disorder is totally cured. A usefulpharmaceutical composition, e.g. a pharmaceutical emulsion composition,herein need only to reduce the severity of the condition or disorder,reduce the severity of symptoms associated therewith, provideimprovement to a patient's quality of life, or delay, prevent or inhibitthe onset of the condition or disorder. A treatment need not beeffective in every member of a population, e.g. a population of patientswith atopic dermatitis, to have clinical utility, as is recognized inthe medical and pharmaceutical arts.

Concentrations, amounts, solubilities, and other numerical data may bepresented herein in a range format. It is to be understood that suchrange format is used merely for convenience and brevity and should beinterpreted flexibly to include not only the numerical values explicitlyrecited as the limit of the range, but also to include all theindividual numerical values or sub-ranges encompassed within that rangeas if each numerical value and sub-range is explicitly recited. Allnumbers expressing quantities, percentages or proportions, and othernumerical values used in the specification, are to be understood asbeing modified in all instances by the term “about”.

For example, a concentration range of 0.1 to 5 ng/ml should beinterpreted to include not only the explicitly recited concentrationlimits of 0.1 ng/ml and 5 ng/ml but also to include individualconcentrations such as 0.2 ng/ml, 0.8 ng/ml, 1.0 ng/ml 2.2 ng/ml, 3.6ng/mol, and sub-ranges such as 0.3-2.5 ng/ml, 1.8-3.2 ng/ml, etc. Thisinterpretation should apply regardless of the breadth of the range orthe characteristic being described.

Any concentration range, percentage range or ratio range recited hereinis to be understood to include concentrations, percentages or ratios ofany integer within that range and fractions thereof, such as one tenthand one hundredth of an integer, unless otherwise indicated.

Other terms used herein are intended to be defined by their well-knownmeanings in the art.

The alternative definitions for the various groups and substituentgroups of Formula (I), Formula (Ia) and Formula (II) provided throughoutthe specification are intended to particularly describe each compoundspecies disclosed herein, individually, as well as groups of one or morecompound species. The scope of this invention includes any combinationof these group and substituent group definitions.

Compounds

In some embodiments, the present disclosure describes a compound ofFormula (I):

or a salt, solvate or hydrate thereof.

Each of substituents R¹ and R² of Formula (I) is independently selectedfrom the group consisting of OH, OR⁷, and H, provided that at least oneof R¹ and R² is OH or OR⁷.

Substituent R⁷ of Formula (I) is independently selected from the groupconsisting of optionally substituted C₁₋₆ alkyl, optionally substitutedC₃₋₆ cycloalkyl, optionally substituted aryl, optionally substitutedaryl C₁₋₆ alkyl and acyl.

Substituent R³ of Formula (I) is selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted aryl,optionally substituted aryl C₁₋₆ alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substituted C₄₋₆ cycloalkenyl, halo, cyano,—C(O)OR⁸, —NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰, —C(O)R¹¹, —OR¹², —S(O)_(n)R¹³, andoptionally substituted heterocyclic ring.

The substituent R⁸ of Formula (I) is independently selected from thegroup consisting of H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₆ cycloalkyl, optionally substituted aryl, and optionallysubstituted aryl C₁₋₆ alkyl;

Each of R⁹ and R¹⁰ of Formula (I) is independently selected from thegroup consisting of H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₆ cycloalkyl, optionally substituted aryl, and optionallysubstituted aryl C₁₋₆ alkyl. Alternatively, substituents R⁹ and R¹⁰together with the nitrogen atom to which they are attached, form a 5-7membered cyclic saturated or unsaturated ring.

Substituent R¹¹ of Formula (I) is independently selected from the groupconsisting of hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted aryl, optionally substituted aryl C₁₋₆ alkyl,optionally substituted C₃₋₆ cycloalkyl, —NR⁹R¹⁰ , and —OR¹².

Each of substituents R¹² and R¹³ of Formula (I) is independentlyselected from the group consisting of H, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted aryl C₁₋₆ alkyl, andoptionally substituted C₃₋₆ cycloalkyl.

Substituent R⁶ of Formula (I) is selected from the group consisting ofH, halo, hydroxyl, alkoxy, optionally substituted C₁₋₆ alkyl,halogenated alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, and optionally substituted aryl C₁₋₆ alkyl.

Subscript n of Formula (I) is an integer having a value of 0, 1 or 2.

Subscript s of Formula (I) is an integer having a value of 0, 1 or 2.

Subscript t of Formula (I) is an integer having a value of 0 to 6.

The substituent R⁵ of Formula (I) is selected from the group consistingof H, halo, optionally substituted C₁₋₆ alkyl, —C(O)OR¹⁴, —C(O)NR¹⁵R¹⁶,optionally substituted aryl, and optionally substituted —C₁₋₆ alkylaryl.

Substituent R¹⁴ of Formula (I) is selected from the group consisting ofH, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substituted aryl, and optionally substituted arylC₁₋₆ alkyl.

Each of substituents R¹⁵ and R¹⁶ of Formula (I) is independentlyselected from the group consisting of H, optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₆ cycloalkyl, optionally substitutedaryl, optionally substituted aryl C₁₋₆ alkyl, and optionally substitutedC₃₋₆ cycloalkyl. Alternatively, R¹⁵ and R¹⁶ together with the nitrogento which they are attached, forms a 5-7 membered cyclic saturated orunsaturated ring.

Substituent R⁴ of Formula (I) is selected from the group consisting ofH, halo, cyano, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted aryl, optionally substituted aryl C₁₋₆ alkyl,optionally substituted C₃₋₆ cycloalkyl, —(CR¹⁸R¹⁹)_(t)COOR⁸,—(CR¹⁸R¹⁹)_(t) OC(O)R⁸; —(CR¹⁸R¹⁹)_(t)NR⁹R¹⁰, —(CR¹⁸R¹⁹)_(t)C(O)NR⁹R¹⁰,—(CR¹⁸R¹⁹)_(t)NR⁹C(O)R⁸, —(CR¹⁸R¹⁹)_(t)S(O)₂NR⁹R¹⁰, —(CR¹⁸R¹⁹)_(t)COR¹¹,—(CR¹⁸R¹⁹)_(t)CH(O), —(CR¹⁸R¹⁹)_(t)OR¹², —(CR¹⁸R¹⁹)_(t)S(O)_(s)R¹³;optionally substituted heterocyclic and optionally substitutedheterocyclicC₁₋₆ alkyl.

Each of substituent R¹⁸ and R¹⁹ of Formula (I) is independently selectedfrom the group consisting of H, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₆ cycloalkyl, optionally substituted aryl, andoptionally substituted aryl C₁₋₆ alkyl.

In some embodiments, the salt is a pharmaceutically acceptable salt.

In some embodiments each of R¹ and R² is independently OH. In someembodiments, one of R¹ and R² is OH and the other is H. In someembodiments, one of R¹ and R² is OH and the other is OR⁷ and in someembodiments both R¹ and R² are OR⁷ wherein each R⁷ is independentlyselected from the group consisting of optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₆ cycloalkyl, optionally substituted aryl,optionally substituted aryl C₁₋₆ alkyl and acyl. In some embodiments, R⁷is optionally substituted C₁₋₄ alkyl. In some embodiments, R⁷ is methylor ethyl. In other embodiments, R⁷ is optionally substituted C₁₋₄ alkylsubstituted with NR²²R²³. In some embodiments, each of R²² and R²³ isindependently selected from the group consisting of H and C₁₋₃ alkyl,such as —(CH₂)₃NH₂. In some embodiments each of R¹ and R² is methoxy. Insome embodiments R¹ and R² is OH and R² is OR⁷, wherein R⁷ is asubstituted C₁₋₆ alkyl. In some embodiments R¹ is OH and R² is OR⁷,wherein R⁷ is C₁₋₆ alkyl substituted with NR²²R²³. In some embodimentsR¹ is OH and R² is —O(CH₂)₃NH₂.

When R⁷ is an optionally substituted moiety, the moiety beingsubstituted may be optionally substituted one or more times, such as oneto three times, independently with halo; hydroxyl; hydroxy substituted—C₁₋₃ alkyl; C₁₋₃ alkoxy; halosubstituted C₁₋₃ alkoxy; —S(O)_(m)C₁₋₃,wherein m is an integer having a value of 0, 1 or 2; —NR²²R²³, whereinR²² and R²³ are independently selected from H or a C₁₋₃ alkyl or whereinR²² and R²³ together with the nitrogen to which they are attached form a5 to 7 membered ring which optionally contains an additional heteroatomselected from O, N, or S; C₃₋₇ cycloalkyl; halosubstituted C₁₋₃ alkyl,such as CF₂CF₂H, or CF_(3;) or optionally substituted aryl, wherein thearyl moiety may also be optionally substituted one to two times by halo;hydroxyl; hydroxy substituted —C₁₋₃ alkyl; C₁₋₃ alkoxy; —S(O)mC₁₋₃alkyl, wherein m is an integer having a value of 0, 1 or 2; amino; monoand di-substituted C₁₋₃ alkylamino; C₁₋₃ alkyl; or CF₃.

In some embodiments R⁷ is optionally substituted C₁₋₆ alkyl. In someembodiments R⁷ is C₁₋₆ alkyl substituted with NR²²R²³. In someembodiments R⁷ is C₁₋₆ alkyl substituted with NH₂. In some embodimentsR⁷ is —(CH₂)₃NH₂.

In some embodiments, when R³ is an optionally substituted moiety, themoiety may be substituted independently one or more times, such as oneto three times. In some embodiments, the moieties may be optionallysubstituted independently one to three times with halo, hydroxy, C₁₋₃alkoxy, C₁₋₃ alkyl, aryl or arylalkyl.

In some embodiments R³ is selected from the group consisting ofoptionally substituted C₃₋₆ alkyl and optionally substituted C₃₋₆cycloalkyl. In some embodiments, the C₃₋₆ alkyl is isopropyl, n-propyl,n-butyl, t-butyl, sec-butyl, n-pentyl, isopentyl, 2-methylbutyl,n-hexyl, and the like. In some embodiments, the alkyl is isopropyl ort-butyl. In some embodiments, the C₃₋₆ alkyl is isopropyl. In someembodiments, the C₃₋₆ cycloalkyl is a cyclopropyl, cyclopentyl orcyclohexyl. In some embodiments, the C₃₋₆ cycloalkyl is cyclopentyl.

In some embodiments R³ is a heterocyclic ring.

In some embodiments R³ is isopropyl.

In some embodiments, R⁶ is selected from the group consisting of H,halo, hydroxyl, C₁₋₃ alkoxy, optionally substituted C₁₋₆ alkyl,halogenated alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, and optionally substituted aryl C₁₋₆ alkyl. Insome embodiments R⁶ is selected from the group consisting of H, halo,hydroxyl, C₁₋₃ alkoxy, optionally substituted C₁₋₃ alkyl, andhalogenated alkyl. In some embodiments, R⁶ is selected from the groupconsisting of H and halo. In some embodiments, R⁶ is selected from thegroup consisting of H and bromo. In some embodiments, R⁶ is H.

In some embodiments R⁵ is selected from the group consisting of H, halo,optionally substituted —C₁₋₆ alkyl, —C(O)OR¹⁴, —C(O)NR¹⁵R¹⁶, aryl and—C₁₋₆ alkylaryl. In some embodiments, R⁵ is selected from the groupconsisting of H, halo, optionally substituted C₁₋₆ alkyl, C(O)OR¹⁴ , andC(O)NR¹⁵R¹⁶. In some embodiments, R⁵ is selected from the groupconsisting of H, halo, optionally substituted C₁₋₆ alkyl, and C(O)OR¹⁴ .In some embodiment, R⁵ is selected from the group consisting of H andoptionally substituted C₁₋₆ alkyl. In some embodiments, R⁵ is selectedfrom the group consisting of H, C(O)OR¹⁴ , and C(O)NR¹⁵R¹⁶. In someembodiments, R⁵ is optionally substituted C₁₋₃ alkyl. In someembodiments when R⁵ is an optionally substituted —C₁₋₆ alkyl moiety, the—C₁₋₆ alkyl is optionally substituted one to three times, independentlywith halo; hydroxyl; C₁₋₃ alkoxy; halosubstituted C₁₋₃ alkoxy;—S(O)mC₁₋₃ alkyl, wherein m is an integer having a value of 0, 1 or 2;—NR²⁰R²¹, wherein R²⁰ and R²¹ are independently selected from the groupconsisting of H and C₁₋₃ alkyl; halo substituted C₁₋₃ alkyl, such asCF₂CF₂H, or CF₃; or aryl. In some embodiments, R⁵ is H.

In some embodiments, R⁴ is selected from the group consisting of H,—(CR¹⁸R¹⁹)_(t)COOR⁸, —(CR¹⁸R¹⁹)_(t)C(O)NR⁹R¹⁰, —(CR¹⁸R¹⁹)_(t)NR⁹R¹⁰,optionally substituted C₁₋₆ alkyl, —(CR¹⁸R¹⁹)_(t)OR¹² and—(CR¹⁸R¹⁹)_(t)S(O)_(s)R¹³. In some embodiments, R⁴ is selected from thegroup consisting of H, —(CR¹⁸R¹⁹)_(t)COOR⁸, and —(CR¹⁸R¹⁹)_(t)C(O)NR⁹R¹⁰; wherein t is 0, R⁹ is H and R¹⁰ is optionally substituted C₁₋₆ alkyl.In some embodiments R⁴ is selected from the group consisting of H,—COOH, —COOCH₃ and —CONH(CH₂)₂NH₂. In some embodiments R⁴ is H.

In some embodiments, t is an integer having a value of 0, 1, 2, or 3. Insome embodiments, t is 0.

In some embodiments, each of R⁹ and R¹⁰ is independently selected fromthe group consisting of H and optionally substituted C₁₋₆ alkyl.

In some embodiments, R¹¹ is selected from the group consisting of H, andoptionally substituted C₁₋₆ alkyl.

In some embodiments, each of R¹² and R¹³ is independently selected fromthe group consisting of H and optionally substituted alkyl.

In some embodiments, n is 0 or 2. In some embodiments, n is 0. In someembodiments, n is 2.

In some embodiments, each of R¹⁸ and R¹⁹ independently selected from thegroup consisting of H and optionally substituted C₁₋₆ alkyl.

Some embodiments describe a compound of Formula (I) wherein:

R¹ is selected from the group consisting of OH and OR⁷, wherein R⁷ isoptionally substituted C₁₋₆ alkyl;

R² is selected from the group consisting of OH and OR⁷, wherein R⁷ isoptionally substituted C₁₋₆ alkyl;

R³ is optionally substituted C₁₋₆ alkyl;

R⁴ is selected from the group consisting of H, —(CR¹⁸R¹⁹)_(t)COOR⁸,—(CR¹⁸R¹⁹)_(t)C(O)NR⁹R¹⁰; wherein t is 0, R⁸ is selected from H andoptionally substituted C₁₋₆ alkyl, R⁹ is H and R¹⁰ is optionallysubstituted C₁₋₆ alkyl;

R⁵ is H; and

R⁶ is H or halo.

Some embodiments describe a compound of Formula (I) wherein:

R¹ is selected from the group consisting of OH and OR⁷, wherein R⁷ isalkyl;

R² is selected from the group consisting of OH and OR⁷, wherein R⁷ isC₁₋₆ alkyl substituted with NR²²R²³; wherein R²² and R²³ areindependently selected from the group consisting of H and C₁₋₃ alkyl;

R³ is optionally substituted C₁₋₆ alkyl;

R⁴ is selected from the group consisting of H, —COOH, —COOCH₃, and—C(O)NR⁹R¹⁰; wherein R⁹ is H; and R¹⁰ is selected from the groupconsisiting of amino substituted C₁₋₆ alkyl and —(CH₂)₂NHC(O)O-t-butyl;

R⁵ is H; and

R⁶ is selected from the group consisting of H and halo.

Some embodiments describe a compound of Formula (I) wherein:

R¹ is selected from the group consisting of OH and —OCH_(3;)

R² is selected from the group consisting of OH, —OCH₃ and —O—(CH₂)₃NH₂;

R³ is C₁₋₆ alkyl;

R⁴ is selected from the group consisting of H, —COOH, —COOCH₃,—C(O)NH(CH₂)₂NH₂; and —C(O)NH(CH₂)₂NHC(O)O-t-butyl;

R⁵ is H; and

R⁶ is selected from the group consisting of H and bromo.

Some embodiments describe a compound of Formula (I) wherein:

R¹ is selected from the group consisting of OH and —OCH₃;

R² is selected from the group consisting of OH, —OCH₃ and —O—(CH₂)₃NH₂;

R³ is isopropyl;

R⁴ is selected from the group consisting of H, —COOH, —COOCH₃,—C(O)(CH₂)₂NH₂; and —C(O)NH(CH₂)₂NHC(O)O-t-butyl;

R⁵ is H; and

R⁶ is is selected from the group consisting of H and bromo.

In one embodiment, the present disclosure describes a compound ofFormula (Ia):

or a salt, solvate or hydrate thereof.

Each of substituents R^(1a) and R^(2a) of Formula (Ia) is independentlyselected from the group consisting of OH, OR^(7a), and H, provided thatat least one of R^(1a) and R^(2a) is OH or OR^(7a).

Substituent R^(7a) of Formula (Ia) is selected from the group consistingof optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substituted aryl, optionally substituted arylC₁₋₆ alkyl and acyl.

Substituent R^(3a) of Formula (Ia) is selected from the group consistingof optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substitutedaryl, optionally substituted aryl C₁₋₆ alkyl, optionally substitutedC₃₋₆ cycloalkyl, optionally substituted C₄₋₆ cycloalkenyl, halo, andoptionally substituted heterocyclic ring.

Substituent R^(6a) of Formula (Ia) is selected from the group consistingof H, halo, hydroxyl, alkoxy, optionally substituted C₁₋₆ alkyl,halogenated alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, and optionally substituted aryl C₁₋₆ alkyl.

The substituent R^(5a) of Formula (Ia) is selected from the groupconsisting of H, halo, optionally substituted C₁₋₆ alkyl, —C(O)OR^(14a), —C(O)NR^(15a)R^(16a), optionally substituted aryl, and optionallysubstituted —C₁₋₆ alkylaryl.

Substituent R^(14a) of Formula (Ia) is independently selected from thegroup consisting of H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₆ cycloalkyl, optionally substituted aryl, and optionallysubstituted aryl C₁₋₆ alkyl.

Each of substituents R^(15a) and R^(16a) of Formula (Ia) isindependently selected from the group consisting of H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,optionally substituted aryl, optionally substituted aryl C₁₋₆ alkyl, andoptionally substituted C₃₋₆ cycloalkyl. Alternatively, R^(15a) andR^(16a) together with the nitrogen to which they are attached, forms a5-7 membered cyclic saturated or unsaturated ring.

Subscript s′ of Formula (Ia) is an integer having a value of 0, 1 or 2.

Subscript t′ of Formula (Ia) is an integer having a value of 0 to 6.

Substituent R^(4a) of Formula (Ia) is selected from the group consistingof H, halo, cyano, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted aryl, optionally substituted aryl C₁₋₆ alkyl,optionally substituted C₃₋₆ cycloalkyl, —(CR^(18a)R^(19a))_(t)COOR^(8a), —(CR^(18a)R^(19a))_(t)OC(O)R^(8a); —(CR^(18a)R^(19a))_(t′),NR9R10, —(CR^(18a)R^(19a))_(t′)C(O)NR^(9a)R^(10a),—(CR^(18a)R^(19a))_(t′)NR^(9a)C(O)R^(8a),—(CR^(18a)R^(19a))_(t′)S(O)₂NR^(9a)R^(10a),—(CR^(18a)R^(19a))_(t′)R^(19a))_(t′)COR^(11a),—(CR^(18a)R^(19a))_(t′)CH(O), —(CR^(18a)R^(19a))_(t′)OR^(12a),—(CR^(18a)R^(19a))_(t′)S(O)_(s′)R^(13a); optionally substitutedheterocyclic and optionally substituted heterocyclicC₁₋₆ alkyl.

Each of substituent R^(18a) and R^(19a) of Formula (Ia) is independentlyselected from the group consisting of H, optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₆ cycloalkyl, optionally substitutedaryl, and optionally substituted aryl C₁₋₆ alkyl.

The substituent R^(8a) of Formula (Ia) is independently selected fromthe group consisting of H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₆ cycloalkyl, optionally substituted aryl, and optionallysubstituted aryl C₁₋₆ alkyl.

Each of substituents R^(9a) and R^(10a) of Formula (Ia) is independentlyselected from the group consisting of H, optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₆ cycloalkyl, optionally substitutedaryl, and optionally substituted aryl C₁₋₆ alkyl. Alternatively,substituents R^(9a) and R^(10a) together with the nitrogen atom to whichthey are attached, form a 5-7 membered cyclic saturated or unsaturatedring.

Substituent R^(11a) of Formula (Ia) is independently selected from thegroup consisting of hydrogen, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted aryl, optionally substituted aryl C₁₋₆alkyl, optionally substituted C₃₋₆ cycloalkyl, —NR^(9a)R^(10a) and—OR^(12a).

Each of substituents R^(12a) and R^(13a) of Formula (Ia) isindependently selected from the group consisting of H, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedaryl C₁₋₆ alkyl, and optionally substituted C₃₋₆ cycloalkyl.

In some embodiments, the salt of Formula (Ia) is a pharmaceuticallyacceptable salt.

In some embodiments, each of R^(1a) and R^(2a) is independently OH. Insome embodiments, one of R^(1a) and R^(2a) is OH and the other is H. Insome embodiments, one of R^(1a) and R^(2a) is OH and the other isOR^(7a) and in some embodiments each of R^(1a) and R^(2a) isindependently OR^(7a), wherein each R^(7a) is independently selectedfrom the group consisting of optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₆ cycloalkyl, optionally substituted aryl,optionally substituted aryl C₁₋₆ alkyl and acyl. In some embodiments,R^(7a) is an optionally substituted C₁₋₄ alkyl. In some embodiments,R^(7a) is methyl or ethyl.

In some embodiments, R^(3a) is selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, and optionally substituted C₃₋₆cycloalkyl. In some embodiments, R^(3a) is optionally substituted C₃₋₆alkyl. In some embodiment, R^(3a) is isopropyl. In some embodiments,R^(3a) is optionally substituted C₃₋₆ cycloalkyl. In some embodiments,the cycloalkyl is cyclopentyl.

In some embodiments, R^(3a) is selected from the group consisting ofoptionally substituted C₃₋₆ alkyl, and optionally substituted C₃₋₆cycloalkyl; and R^(1a) and R^(2a) are each independently OH. In someembodiments, R^(3a) is selected from the group consisting of optionallysubstituted C₃₋₆ alkyl, and optionally substituted C₃₋₆ cycloalkyl; andeach of R^(1a) and R^(2a) is independently selected from the groupconsisting of OH, OR^(7a), and H, provided that at least one of R^(1a)and R^(2a) is OH or OR^(7a). In another embodiment, R^(3a) is selectedfrom the group onsisting of optionally substituted C₃₋₆ alkyl andoptionally substituted C₃₋₆ cycloalkyl; and one of R^(1a) and R^(2a) isOH and the other is H.

In some embodiments, each of R^(4a) and R^(5a) is independently selectedfrom H and halo.

In some embodiments, R^(4a) is H, and R^(5a) is selected from the groupconsisting of H, halo, optionally substituted C₁₋₆ alkyl, C(O)OR^(14a),and C(O)NR^(15a)R^(16a). In some embodiments, R^(5a) is H, and R^(4a) isselected from the group consisting of H, halo, optionally substitutedC₁₋₆ alkyl, C(O)OR^(14a), and C(O)NR^(15a)R^(16a).

In some embodiments, R^(3a) is selected from the group consisting ofoptionally substituted C₃₋₆ alkyl and optionally substituted C₃₋₆cycloalkyl; both R^(1a) and R^(2a) are OH, and each of R^(4a) and R^(5a)is independently selected from H and halo.

In some embodiments, R^(3a) is an optionally substituted C₃₋₆ alkyl,each of R^(1a) and R^(2a) is OH, and each of R^(4a) and R^(5a) isindependently H or halo.

In some embodiments, R^(6a) is independently selected from the groupconsisting of H, halo, hydroxyl, C₁₋₆ alkoxy, optionally substitutedC₁₋₆ alkyl, halogenated alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, and optionally substituted arylC₁₋₆ alkyl. In some embodiments, R^(6a) is selected from the groupconsisting of H, halo, hydroxyl, C₁₋₃ alkoxy, optionally substitutedC₁₋₃ alkyl, and halogenated alkyl. In some embodiments, R^(6a) isselected from the group consisting of H and halo. In some embodiments,R^(6a) is H.

In some embodiments, R^(6a) is selected from the group consisting of Hand halo; R^(3a) is an optionally substituted C₃₋₆ alkyl, each of R^(1a)and R^(2a) is OH, and each of R^(4a) and R^(5a) is independentlyselected from the group consisting of H and halo

In some embodiments, t is 0. In some embodiments, t is 0, 1, 2, or 3.

Some embodiments of the invention are directed to a compound of selectedfrom the group consisting of:

or a salt, solvate or hydrate thereof.

Some embodiments of the invention are directed to2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In some embodiments the2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, is a solid. In someembodiments the solid is a crystalline solid. In some embodiments thesolid is an amorphous solid. In some embodiments the2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol is a non-solvatedcrystal. Some embodiments describe isolated2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol. In some embodimentsthe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol is a hydrate. Insome embodiments the 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol isan organic solvate. Some embodiments describe isolated2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol organic solvate. Someembodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene- 1,3-diolacetonitrile/water solvate. Some embodiments describe2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol acetone solvate. Someembodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diolN,N-dimethylformamide solvate. Some embodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 1,4-dioxane/water solvate. Someembodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diolbutanone solvate. Some embodiments describe2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol tetrahydrofuran/watersolvate. Some embodiments describe2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol ethylacetate solvate.Some embodiments describe2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol dimethylcarbonatesolvate. Some embodiments describe2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol dimethylsulfoxidesolvate. Some embodiments describe2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 1-butanol solvate. Someembodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-dioltetrahydrofuran solvate. Some embodiments describe2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol methyl t-butyl ethersolvate.

The invention also includes various isomers of a compound according toany embodiment described herein, and mixtures thereof. Isomers arecompounds that have the same composition and molecular weight but differin physical and/or chemical properties. The structural difference may bein constitution (geometric isomers) or in the ability to rotate theplane of polarized light (stereoisomers). A compound according to anyembodiment described herein, may contain one or more asymmetric centers,also referred to as chiral centers, and may, therefore, exist asindividual enantiomers, diastereomers, or other stereoisomeric forms, oras mixtures thereof. All such isomeric forms are included within thepresent invention, including mixtures thereof. Chiral centers may alsobe present in a substituent such as an alkyl group. Where thestereochemistry of a chiral center present in a formula, or in anychemical structure illustrated herein, is not specified the structure isintended to encompass any stereoisomer and all mixtures thereof. Thus, acompound according to any embodiment described herein, containing one ormore chiral centers may be used as racemic mixtures, enantiomericallyenriched mixtures, or as enantiomerically pure individual stereoisomers.A mixture containing unequal portions of the enantiomers is described ashaving an “enantiomeric excess” (ee) of either the R or S compound. Theexcess of one enantiomer in a mixture is often described with a %enantiomeric excess. The ratio of enantiomers can also be defined by“optical purity” wherein the degree at which the mixture of enantiomersrotates plane polarized light is compared to the individual opticallypure R and S compounds. The compounds can also be a substantially pure(+) or (−) enantiomer of the compounds described herein. In someembodiments, a composition can include a substantially pure enantiomerof a compound according to any embodiment described herein, that is atleast 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of oneenantiomer. In certain embodiments, a composition may include asubstantially pure enantiomer of a compound according to any embodimentdescribed herein, that is at least 99.5% of one enantiomer.

Individual stereoisomers of a compound according to any embodimentdescribed herein, which contain one or more asymmetric centers may beresolved by methods known to those skilled in the art. For example, suchresolution may be carried out (1) by formation of diastereoisomericsalts, complexes or other derivatives; (2) by selective reaction with astereoisomer specific reagent, for example by enzymatic oxidation orreduction; or (3) by gas-liquid or liquid chromatography in a chiralenvironment, for example, on a chiral support such as silica with abound chiral ligand or in the presence of a chiral solvent. The skilledartisan will appreciate that where the desired stereoisomer is convertedinto another chemical entity by one of the separation proceduresdescribed above, a further step is required to liberate the desiredform. Alternatively, specific stereoisomers may be synthesized byasymmetric synthesis using optically active reagents, substrates,catalysts or solvents, or by converting one enantiomer to the other byasymmetric transformation. Further embodiments include prodrugs of acompound according to any embodiment described herein, i.e. compoundswhich release an active compound according to any of the embodimentsdescribed herein, in vivo when administered to a mammalian subject. Aprodrug is a pharmacologically active or more typically an inactivecompound that is converted into a pharmacologically active agent by ametabolic transformation. Prodrugs of a compound according to anyembodiment described herein, are prepared by modifying functional groupspresent in the compound in such a way that the modifications may becleaved in vivo to release the parent compound. In vivo, a prodrugreadily undergoes chemical changes under physiological conditions (e.g.are hydrolyzed or acted on by naturally occurring enzyme(s)) resultingin liberation of the pharmacologically active agent. Prodrugs includecompounds according to any embodiment described herein, wherein ahydroxyl, amino, or carboxy group is bonded to any group that may becleaved in vivo to regenerate the free hydroxyl, amino or carboxy group,respectively. Examples of prodrugs include, but are not limited toesters (e.g., acetate, formate, and benzoate derivatives) of compoundsaccording to any embodiment described herein, or any other derivativewhich upon being brought to the physiological pH or through enzymeaction is converted to the active parent drug. Conventional proceduresfor the selection and preparation of suitable prodrug derivatives aredescribed in the art.

Certain of the compounds of the invention may form salts with one ormore equivalents of an acid (if the compound contains a basic moiety) ora base (if the compound contains an acidic moiety). The presentinvention includes within its scope all possible stoichiometric andnon-stoichiometric salt forms.

When a compound of the invention contains a basic moiety, a desired saltform may be prepared by any suitable method known in the art, includingtreatment of the free base with an inorganic acid, such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or with an organic acid, such as acetic acid, trifluoroaceticacid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonicacid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, and thelike; or with a pyranosidyl acid, such as glucuronic acid orgalacturonic acid; or with an alpha-hydroxy acid, such as citric acid ortartaric acid; or with an amino acid, such as aspartic acid or glutamicacid; or with an aromatic acid, such as benzoic acid or cinnamic acid;or with a sulfonic acid, such as p-toluenesulfonic acid, methanesulfonicacid, ethanesulfonic acid or the like.

Suitable addition salts are formed from acids which form non-toxic saltsand examples include acetate, p-aminobenzoate, ascorbate, aspartate,benzenesulfonate, benzoate, bicarbonate, bismethylenesalicylate,bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate,clavulanate, citrate, cyclohexylsulfamate, edetate, edisylate, estolate,esylate, ethanedisulfonate, ethanesulfonate, formate, fumarate,gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate,hexylresorcinate, hydrobromide, hydrochloride, dihydrochloride,hydrofumarate, hydrogen phosphate, hydroiodide, hydromaleate,hydrosuccinate, hydroxynaphthoate, isethionate, itaconate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, monopotassium maleate, mucate, napsylate, nitrate,N-methylglucamine, oxalate, oxaloacetate, pamoate (embonate), palmate,palmitate, pantothenate, phosphate/diphosphate, pyruvate,polygalacturonate, propionate, saccharate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate,triethiodide, trifluoroacetate and valerate.

Other exemplary acid addition salts include pyrosulfate, sulfite,bisulfite, decanoate, caprylate, acrylate, isobutyrate, caproate,heptanoate, propiolate, oxalate, malonate, suberate, sebacate,butyne-1,4-dioate, hexyne-1,6-dioate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,phenylacetate, phenylpropionate, phenylbutrate, lactate,γ-hydroxybutyrate, mandelate, and sulfonates, such as xylenesulfonate,propanesulfonate, naphthalene-1-sulfonate and naphthalene-2-sulfonate.

If an inventive basic compound is isolated as a salt, the correspondingfree base form of that compound may be prepared by any suitable methodknown to the art, including treatment of the salt with an inorganic ororganic base, suitably an inorganic or organic base having a higherpK_(a) than the free base form of the compound.

When a compound of the invention contains an acidic moiety, a desiredsalt may be prepared by any suitable method known to the art, includingtreatment of the free acid with an inorganic or organic base, such as anamine (primary, secondary, or tertiary), an alkali metal or alkalineearth metal hydroxide, or the like. Illustrative examples of suitablesalts include celitec salts derived from amino acids such as glycine andarginine, ammonia; primary, secondary, and tertiary amines, and cyclicamines, such as N-methyl-D-glucamine, diethylamine, isopropylamine,trimethylamine, ethylene diamine, dicyclohexylamine, ethanolamine,piperidine, morpholine, and piperazine; as well as inorganic saltsderived from sodium, calcium, potassium, magnesium, manganese, iron,copper, zinc, aluminum, and lithium.

Those compounds of the invention having both a basic and acidic moietymay be in the form of zwitterions, acid-addition salt of the basicmoiety or base salts of the acidic moiety.

Because of their potential use in medicine, the salts of the compoundsof the invention are preferably pharmaceutically acceptable salts.Suitable pharmaceutically acceptable salts are known to those of skillin the art.

These pharmaceutically acceptable salts may be prepared in situ duringthe final isolation and purification of the compound, or by separatelytreating the purified compound in its free acid or free base form with asuitable base or acid, respectively.

In certain embodiments, compounds of the invention may contain an acidicfunctional group and are, therefore, capable of forming pharmaceuticallyacceptable base addition salts by treatment with a suitable base.Examples of such bases include, but are not limited to, a) hydroxides,carbonates, and bicarbonates of sodium, potassium, lithium, calcium,magnesium, aluminum, and zinc; and b) primary, secondary, and tertiaryamines including aliphatic amines, aromatic amines, aliphatic diamines,and hydroxy alkylamines such as methylamine, ethylamine,2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine,ethanolamine, diethanolamine, and cyclohexylamine.

In certain embodiments, compounds of the invention may contain a basicfunctional group and are therefore capable of forming pharmaceuticallyacceptable acid addition salts by treatment with a suitable acid.Suitable acids include pharmaceutically acceptable inorganic acids andorganic acids. Representative pharmaceutically acceptable acids includehydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid,sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid,phenylacetic acid, propionic acid, butyric acid, valeric acid, maleicacid, acrylic acid, fumaric acid, succinic acid, malic acid, malonicacid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannicacid, formic acid, stearic acid, lactic acid, ascorbic acid,methylsulfonic acid, p-toluenesulfonic acid, oleic acid, lauric acid,and the like.

This invention also provides for the conversion of one pharmaceuticallyacceptable salt of a compound of the invention into anotherpharmaceutically acceptable salt of a compound of this invention.

A compound according to any embodiment described herein, may exist insolid or liquid form. In the solid state, it may exist in crystalline ornon-crystalline form, or as a mixture thereof. The skilled artisan willappreciate that pharmaceutically acceptable solvates may be formed fromcrystalline compounds wherein solvent molecules are incorporated intothe crystalline lattice during crystallization. Solvates may involvenon-aqueous solvents such as, but not limited to, ethanol, isopropanol,DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involvewater as the solvent that is incorporated into the crystalline lattice.Solvates wherein water is the solvent incorporated into the crystallinelattice are typically referred to as “hydrates.” Hydrates includestoichiometric hydrates as well as compositions containing variableamounts of water. The invention includes all such solvates.

For solvates of a compound according to any embodiment described herein,including solvates of salts of a compound according to any embodimentdescribed herein, that are in crystalline form, the skilled artisan willappreciate that pharmaceutically acceptable solvates may be formedwherein solvent molecules are incorporated into the crystalline latticeduring crystallization. Solvates may involve non-aqueous solvents suchas ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc, orthey may involve water as the solvent that is incorporated into thecrystalline lattice. Solvates wherein water is the solvent that isincorporated into the crystalline lattice are typically referred to as“hydrates.” Hydrates include stoichiometric hydrates as well ascompositions containing variable amounts of water. The inventionincludes all such solvates.

The skilled artisan will further appreciate that a compound according toany embodiment described herein that exists in crystalline form,including the various solvates thereof, may exhibit polymorphism (i.e.the capacity to occur in different crystalline structures). Thesedifferent crystalline forms are typically known as “polymorphs.” Theinvention includes all such polymorphs. Polymorphs have the samechemical composition but differ in packing, geometrical arrangement, andother descriptive properties of the crystalline solid state. Polymorphs,therefore, may have different physical properties such as shape,density, hardness, deformability, stability, and dissolution properties.Polymorphs typically exhibit different melting points, IR spectra, andX-ray powder diffraction patterns, which may be used for identification.The skilled artisan will appreciate that different polymorphs may beproduced, for example, by changing or adjusting the reaction conditionsor reagents, used in making the compound. For example, changes intemperature, pressure, or solvent may result in polymorphs. In addition,one polymorph may spontaneously convert to another polymorph undercertain conditions.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in compounds of the invention andfollowing, but for the fact that one or more atoms are replaced by anatom having an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention and pharmaceuticallyacceptable salts, solvates or hydrates thereof, include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine,iodine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P,³²P, ³⁵S, ¹⁸F, ³⁶C, ¹²³I and ¹²⁵I.

Compounds according to any embodiment described herein andpharmaceutically acceptable salts, solvates or hydrates of saidcompounds that contain the aforementioned isotopes and/or other isotopesof other atoms are within the scope of the present invention.Isotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H, ¹⁴C are incorporated,are useful in drug and/or substrate tissue distribution assays.Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. ¹¹C and ¹⁸Fisotopes are particularly useful in PET (positron emission tomography),and ¹²⁵I isotopes are particularly useful in SPECT (single photonemission computerized tomography), and are also useful in brain imaging.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds according to any embodiment describedherein, can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples below, by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent.

The invention also embraces isolated compounds. An isolated compoundrefers to a compound which represents at least 10%, preferably at least20%, more preferably at least 50% and most preferably at least 80% ofthe compound present in the mixture.

Because the compounds according to any embodiment described herein areintended for use in pharmaceutical compositions it will readily beunderstood that they are each preferably provided in substantially pureform, for example at least 60% pure, more suitably at least 75% pure andpreferably at least 85%, especially at least 98% pure (% are on a weightfor weight basis). In some embodiments, a compound according to anyembodiment described herein is at least 90%, at least 91%, at least 92%,at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, or at least 99% pure. Impure preparations of the compoundsmay be used for preparing the more pure forms used in the pharmaceuticalcompositions.

Pharmaceutical Compositions

Some embodiments describe a pharmaceutical composition comprising: acompound according to any embodiment described herein, apharmaceutically acceptable salt thereof, a solvate thereof, or ahydrate thereof; and a pharmaceutically acceptable carrier or diluent.The pharmaceutical compositions can be prepared in a manner well knownin the pharmaceutical arts, and can be administered by a variety ofroutes, depending upon whether local or systemic treatment is desiredand upon the area to be treated.

While it is possible that a compound as described in any embodimentherein, may be administered as the bulk substance, it is preferable topresent the compound in a pharmaceutical formulation, e.g., wherein theactive agent is in an admixture with a pharmaceutically acceptablecarrier selected with regard to the intended route of administration andstandard pharmaceutical practice.

In particular, the disclosure provides a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundaccording to any embodiment described herein, and optionally, apharmaceutically acceptable carrier.

Some embodiments describe a pharmaceutical composition comprising2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3 -diol:

or a pharmaceutically acceptable salt, solvate or hydrate thereof and apharmaceutically acceptable carrier or diluent.

Some embodiments describe a pharmaceutical composition comprisingN-(2-aminoethyl)-3-[3,5-dihydroxy-4-(propan-2-yl)phenyl]isoquinoline-6-carboxamide:

or a pharmaceutically acceptable salt, solvate or hydrate thereof and apharmaceutically acceptable carrier or diluent.

Some embodiments describe a pharmaceutical composition comprising3-(3-aminopropoxy)-5-(isoquinolin-3-yl)-2-(propan-2-yl)phenol:

or a pharmaceutically acceptable salt, solvate or hydrate thereof and apharmaceutically acceptable carrier or diluent. In one embodiment, thesalt is trifluroacetic acid salt:

Methods of Treatment

Vitiligo is a depigmentation disorder resulting from selectivedestruction of melanocytes. In melanocytes, AhR links solar UVBradiation to skin pigmentation. A decreased risk of vitiligo associatedwith a specific variant of the AhR gene has been described, and, infurther work, these authors found an AhR variant promoted Ahrtranscriptional activity, facilitating its interaction with the SP1transcripion factor, resulting in increased AhR expression and IL-10production in humans (.

AhR-activating ligands have been shown to reduce inflammation in thelesional skin of patients with psoriasis and AhR antagonists exacerbatedthis disease. AhR signaling via FICZ reduce the inflammation inimiquimod-induced mouse models and AhR-deficient mice showedexacerbation of the disease compared to WT controls. It should also benoted that keratinocytes were implicated to be involved in theinflammatory response.

Activation of the AhR pathway has also been shown to result ininflammatory skin lesions, such as atopic dermatitis, and exacerbationof inflammatory diseases, after exposure to occupation or environmentalxenobiotics. An AhR agonist, coal tar, was shown to completely restoreexpression of major skin barrier proteins.

Early dry age-related macular degeneration (AMD) is the leading cause ofvision loss in the elderly. AhR activity and protein in human retinalpigment epithelial cells decrease with age and AhR(−/−) mice exhibitdecreased visual function and develop dry AMD-like pathology. Anothergroup also showed that Ahr(−/−) mice exhibited subretinal accumulationof microglia and focal retinal pigment epithelial cell atrophy, which isa phenotype observed in AMD.

The Malek lab has found that AhR is also implicated in wet AMD. Theyshowed that in experimentally induced choroidal neovascular lesions inAhR(−/−) mice, there were lesions that displayed a higher number ofionized calcium-binding adaptor molecule 1-positive (Iba1(+)) microglialcells and a greater amount of collagen type IV deposition, all eventsalso seen in human wet AMD.

There are many other potential indications where AhR agonism, orantagonism, may have an effect on disease severity or progression. Thereis also mounting evidence that targeting AhR in other disease conditionsmay be beneficial, such as for treatment of inflammation of the gut asin Irritable bowel disease (IBD), colitis and Crone's disease. AhR hasalso been shown to play an important role in protecting lungs fromallergen-induced inflammation by modulating MSC recruitment and theirimmune-suppressive activity.

Atopic dermatitis (AD) is an intensely pruritic, chronic, relapsing,inflammatory skin disease. The cause of atopic dermatitis ismultifactorial, with genetic and environmental factors, deficient skinbarrier function, and an impaired immune response being the mostpredominant factors. The impaired immune response is characterized byactivation of T-helper type 2 (Th2) cells with an increase in IgEproduction; there is also an over-expression of eotaxin-3, IL-2, IL-5,and IL-13 in skin lesions. The inflammatory component of atopicdermatitis is also thought to be mediated primarily by the Th2 type Tcell activation pathway, although in chronic atopic dermatitis skinlesions, a shift towards a T-helper type 1 (Th1) driven pathway has beendescribed. Atopic dermatitis often occurs in families with other atopicconditions, supporting the hypothesis that it may be genetically linked.

Skin barrier dysfunction is one of the critical factors in thepathogenesis of atopic dermatitis. The characteristic signs and symptomsof atopic dermatitis include sensations of pruritus and burning,lichenification, and xerosis, with erythematous papules and plaques,vesiculation, exudation and crusting, erosion, and scaling. Atopicdermatitis often has a major impact on quality of life, because of boththe stigma associated with having a visible skin lesion and the intenseand constant itching that leads to sleep deprivation.

To date, there is no curative therapy for atopic dermatitis. Stabilizingthe disease and reducing the number and severity of flares are theprimary goals of treatment for both pediatric and adult patients.Patients require treatment of acute flares and, in persistent cases,long-term maintenance therapy. Topical therapies are directed at skininflammation and are a key factor in disease management, as issymptomatic relief of itching in atopic dermatitis. Although multipletopical treatment options are available, there remains a need for atopical treatment that combines a high level of efficacy with anacceptable adult and pediatric safety profile that permits applicationto a large body surface area without restrictions on duration oftreatment. Topical corticosteroids (TCSs) are typically the standard ofcare for acute flares of atopic dermatitis.

However, TCSs are not generally suitable for long-term use due to thepotential for local and systemic adverse events (e.g., skin atrophy andincreased risk of systemic exposure). Current treatment options foratopic dermatitis in children are especially limited, given the safetyconcerns of long-term use (>2-4 weeks) or application to sensitive areassuch as the face or intertriginous regions.

Without wishing to be bound by any theory, compounds according toembodiments described herein, are believed to have a different mechanismof action than topical corticosteroids (TCSs) and topical calcineurininhibitors (TCIs), and are expected to have an improved safety profilewith efficacy superior to TCIs. The compounds of embodiments describedherein, would provide benefit to children who: are not adequatelyresponsive to TCS; are intolerant to TCS; or are not indicated for TCS(e.g., due to lesion location or treatment duration). Having aneffective option for a safe topical treatment may delay the transitionto systemic therapies, limiting significant risks associated withtreatment as well as costs to the patient.

Psoriasis vulgaris is a chronic autoimmune inflammatory skin disorderthat results from an interaction of genetic, environmental and systemicfactors and affects 2-3% of the Caucasian population. Immune systemdysregulation is implicated in disease pathogenesis and includesaberrant cellular infiltrates, production of inflammatory mediators, andkeratinization. At the crux of this process are the Th17-type cytokines(IL-17A, IL-17F and IL-22) which (i) drive keratinocytehyperproliferation and chemokine production, and (ii) perpetuate furtherleukocyte recruitment.

Compounds according to embodiments described herein may be used be usedfor the treatment of mild to moderate psoriasis. Although there havebeen numerous new biological treatment options for severe psoriasis,there has been limited recent innovation in treatment options forpatients with mild to moderate disease. Treatment with TCSs carrysignificant contraindications (long-term use and use in sensitiveareas), thus a safe and effective topical treatment would be atremendous advantage for mild to moderate psoriasis patients.

The present invention thus provides methods for the treatment ofdisorders associated with the abovementioned diseases or disorders,comprising the step of administering to a subject in need thereof atleast one compound, as described in any embodiment herein, in an amounteffective therefore.

In some embodiments, the disclosure provides methods of preventing ortreating a condition associated with an AhR imbalance.

In some embodiments, the disclosure provides methods of treating orpreventing an AhR mediated disease in a subject in need thereof,comprising administering to said subject an effective amount of acompound according to any embodiment described herein, orpharmaceutically acceptable salt, solvate or hydrate thereof or apharmaceutical composition according to any embodiment described herein.In some embodiments the compound is a compound of Formula (I) or Formula(Ia) or a pharmaceutically acceptable salt, solvate or hydrate thereof.In some embodiments the compound is a compound of Formula (I) or Formula(Ia), or a pharmaceutically acceptable salt, solvate or hydrate thereofin combination with another therapeutic agent. In some embodiments thecompound is 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or apharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof in combination with anothertherapeutic agent.

Some embodiments describe a method for treating or preventing disorderssuch as: clinical transplants (such as organ transplant, acutetransplant or heterograft or homograft (such as is employed in burntreatment) rejection; protection from ischemic or reperfusion injurysuch as ischemic or reperfusion injury incurred during organtransplantation, myocardial infarction, stroke or other causes;transplantation tolerance induction; arthritis (such as rheumatoidarthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis;IBD, including ulcerative colitis and Crohn's disease; lupus (systemiclupus erythematosis); graft vs. host disease; T-cell mediatedhypersensitivity diseases, including contact hypersensitivity, eczema,delayed-type hypersensitivity, and gluten-sensitive enteropathy (Celiacdisease); psoriasis; contact dermatitis (including that due to poisonivy); Hashimoto's thyroiditis; Sjogren's syndrome; autoimmunehyperthyroidism, such as Graves' Disease; Addison's disease (autoimmunedisease of the adrenal glands); autoimmune polyglandular disease (alsoknown as autoimmune polyglandular syndrome); autoimmune alopecia;pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain-Barresyndrome; other autoimmune diseases; glomerulonephritis, serum sickness;uticaria; allergic diseases such as respiratory allergies (asthma, hayfever, allergic rhinitis) or skin allergies; scleracierma; mycosisfungoides; acute inflammatory responses (such as acute respiratorydistress syndrome and ishchemia/reperfusion injury); dermatomyositis;alopecia greata; chronic actinic dermatitis; eczema; Behcet's disease;Pustulosis palmoplanteris; Pyoderma gangrenum; Sezary's syndrome; atopicdermatitis; systemic sclerosis; and morphea; comprising administering aneffective amount of a compound according to any embodiment describedherein, or pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition, according to any embodiment described herein.

Some embodiments describe a method for treating or preventing anallergic disease or disorder, an inflammatory disease or disorder or anautoimmune disease or disorder in a subject in need thereof, comprisingadministering to said subject an effective amount of a compoundaccording to any embodiment described herein, or pharmaceuticallyacceptable salt, solvate or hydrate thereof. In some embodiments thecompound is a compound of Formula (I) or Formula (Ia) or apharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments the compound is a compound of Formula (I) or Formula (Ia) orpharmaceutically acceptable salt, solvate or hydrate thereof incombination with another therapeutic agent. In some embodiments thecompound is 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or apharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof in combination with anothertherapeutic agent.

Some embodiments describe a method for treating or preventing aninflammatory disease or disorder in a subject in need thereof,comprising administering to said subject an effective amount of acompound or pharmaceutical composition according to any embodimentdescribed herein, or pharmaceutically acceptable salt, solvate orhydrate thereof. In some embodiments the compound is a compound ofFormula (I) or Formula (Ia) or a pharmaceutically acceptable salt,solvate or hydrate thereof. In some embodiments the compound is acompound of Formula (I) or Formula (Ia) or pharmaceutically acceptablesalt, solvate or hydrate thereof in combination with another therapeuticagent. In some embodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof. In some embodiments thecompound is 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or apharmaceutically acceptable salt, solvate or hydrate thereof incombination with another therapeutic agent.

In some embodiments the inflammatory disease or disorder is aninflammatory skin disease or disorder. In some embodiments theinflammatory skin disease or disorder is a chronic inflammatory skindisease or disorder, acne, psoriasis, rosacea or aging skin. In someembodiments the chronic inflammatory skin disease is dermatitis, e.g.atopic dermatitis, contact dermatitis, eszematous dermatitis, orseborrheic dermatitis.

In some embodiments, the inflammatory disease or disorder is selectedfrom the group consisting of psoriasis, atopic dermatitis, contactdermatitis, eczematous dermatitis, or seborrhoic dermatitis and acne. Insome embodiments, the inflammatory disease or disorder is selected fromthe group consisting of psoriasis, atopic dermatitis, and acne. In someembodiments, the inflammatory disease or disorder is psoriasis. In someembodiments, the inflammatory disease or disorder is atopic dermatitis.In some embodiments, the inflammatory disease or disorder is acne.

Some embodiments describe a method for treating or preventing adermatological condition or disorder in a subject in need thereof,comprising administering to said subject an effective amount of acompound or pharmaceutical composition according to any embodimentdescribed herein, or pharmaceutically acceptable salt, solvate orhydrate thereof. In some embodiments the compound is a compound ofFormula (I) or Formula (Ia) or a pharmaceutically acceptable salt,solvate or hydrate thereof. In some embodiments the compound is acompound of Formula (I) or Formula (Ia) or pharmaceutically acceptablesalt, solvate or hydrate thereof in combination with another therapeuticagent. In some embodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof. In some embodiments thecompound is 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or apharmaceutically acceptable salt, solvate or hydrate thereof incombination with another therapeutic agent.

In some embodiments the dermatological condition or disorder is a skindisease. In some embodiments the skin disease is selected from 1) a skindisorder of persistent inflammation, cell kinetics, and differentiation(e.g., psoriasis, psoriatic arthritis, exfoliative dermatitis,pityriasis rosea, lichen planus, lichen nitidus, or porokeratosis); 2) askin disorder of epidermal cohesion, vesicular and bullous disorders(e.g., pemphigus, bulluous pemphigoi, epidermamolysis bullosa acquisita,or pustular eruptions of the palms or soles); 3) a skin disorder ofepidermal appendages and related disorders (e.g., hair disorders, nails,rosacea, perioral dermatitis, or follicular syndromes); 4) a skindisorder such as an epidermal and appendageal tumors (e.g., squamouscell carcinoma, basal cell carcinoma, keratoacanthoma, benign epithelialtumors, or merkel cell carcinoma); 5) a disorder of melanocytes (e.g.,pigmentary disorders, albinism, hypomelanoses and hypermelanoses,melanocytic nevi, or melanoma); 6) a skin disorder of inflammatory andneoplastic disorders of the dermis (e.g., erythema elavatum diutinum,eosinophils, granuloma facilae, pyoderma gangrenosum, malignant atrophicpapulosis, fibrous lesions of dermis and soft tissue, or Kaposisarcoma); 7) a disorder of the subcutaneous tissue (e.g., panninculitisor lipodystrophy); 8) a skin disorder involving cutaneous changes ofaltered reactivity (e.g., urticaria, angiodererma, graft-vs-host,allergic contact dermatitis, autosensitization dermatitis, atopicdermatitis, or seborrheic dermatitis); 9) a skin change due tomechanical and physical factors (e.g., thermal injury, radiationdermatitis, corns, or calluses); 10) photodamage (e.g., acute andchronic UV radiation, or photosensitization); or 11) a skin disorder dueto microbial agents (e.g., leprosy, lyme borreliosis, onychomycosis,tinea pedra, rubella, measles, herpes simplex, Epstein-Barr virus (EBV),Human papillomavirus (HPV, e.g., HPV6 & 7), warts, or prions).

Some embodiments describe a method for treating or preventing aradiation dermatitis in a subject in need thereof, comprisingadministering to said subject an effective amount of a compound orpharmaceutical composition according to any embodiment described herein,or pharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments the compound is a compound of Formula (I) or Formula (Ia) ora pharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments the compound is a compound of Formula (I) or Formula (Ia) orpharmaceutically acceptable salt, solvate or hydrate thereof incombination with another therapeutic agent. In some embodiments thecompound is 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or apharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof in combination with anothertherapeutic agent. In some embodiments the radiation dermatitis ischronic raditation dermatitis. In some embodiments the radiationdermatitis is acute raditation dermatitis. In some embodiments theradiation dermatitis is acute erythema, sale, desquamation, fibrosis,telangiectasias and skin atrophy or combinations thereof. In someembodiments the radiation dermatitis is acute erythema, sale, ordesquamation, or combinations thereof. In some embodiments the radiationdermatitis is fibrosis, telangiectasias and skin atrophy or combinationsthereof.

Some embodiments describe a method for treating or preventing aninflammatory mucosal conditions in a subject in need thereof, comprisingadministering to said subject an effective amount of a compound orpharmaceutical composition according to any embodiment described herein,or pharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments the compound is a compound of Formula (I) or Formula (Ia) ora pharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments the compound is a compound of Formula (I) or Formula (Ia) orpharmaceutically acceptable salt, solvate or hydrate thereof incombination with another therapeutic agent. In some embodiments thecompound is 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or apharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof in combination with anothertherapeutic agent. In some embodiments the inflammatory mucosalcondition is induced by cancer radiation or chemotherapy treatment. Insome embodiments the inflammatory mucosal condition is oral mucositis,lichen planus, pemphigus vulgaris. In some embodiments the inflammatorymucosal condition is an oral mucositis such as oral lichen planus,erythema multiforme, mucous membrane pemphigoid, pemphigus vulgaris,epidermolysis bullosa aquisita. In some embodiments the oral mucositisis induced by cancer radiation or chemotherapy treatment. In someembodiments the oral mucositis is induced by head and/or neck cancerradiation or chemotherapy treatment. In some embodiments the oralmucositis is induced by head and/or neck cancer radiation treatment.

Some embodiments describe a method of treating atopic dermatitis in asubject in need thereof, comprising administering to the subject, atherapeutically effective amount of a compound of the formula

or a pharmaceutically acceptable salt, solvate or hydrate thereof or apharmaceutical composition thereof.

Some embodiments describe a method of treating psoriasis in a subject inneed thereof, comprising administering to the subject, a therapeuticallyeffective amount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol:

or a pharmaceutically acceptable salt, solvate or hydrate thereof or apharmaceutical composition thereof.

Some embodiments describe a method of treating atopic dermatitis in asubject in need thereof, comprising administering to the subject,2-isopropyl-5-(isoquinolin-3 -yl)benzene-1,3 -diol:

or a pharmaceutically acceptable salt, solvate or hydrate thereof or apharmaceutical composition thereof.

Some embodiments describe a method of treating atopic dermatitis orpsoriasis, in a subject in need thereof, comprising administering to thesubject, a topical cream comprising a therapeutically effective amountof 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or apharmaceutically acceptable salt, solvate or hydrate thereof.

Some embodiments describe a method of treating atopic dermatitis orpsoriasis, in a subject in need thereof, comprising administering to thesubject, a topical gel comprising a therapeutically effective amount of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe a method of treating atopic dermatitis orpsoriasis, in a subject in need thereof, comprising administering to thesubject, a topical lotion comprising a therapeutically effective amountof 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or apharmaceutically acceptable salt, solvate or hydrate thereof.

In some embodiments, the compound is an agonist of the AhR ligand. Insome embodiments, the compound is an antagonist of the AhR ligand.

A compound according to any embodiment described herein may be used in aveterinary setting or in a medical setting. It is recognized that thesubject or patient may be an animal, a domestic animal, such as amammal, including horses, cows, pigs, sheep, poultry, fish, cats, dogsand zoo animals. In some embodiment, the subject is an animal.

In some embodiments, the subject is a mammal. In some embodiments, thesubject is a human. In some embodiments, the human is an adult, or apediatric patient. In some embodiments, the human is a pediatricpatient. In some embodiments, the pediatric patient is a child. In someembodiments, the pediatric patient is 3 months to 2 years of age andolder. In some embodiments, the human is an adult.

Some embodiments describe a compound according to any embodimentdescribed herein, or pharmaceutically acceptable salt, solvate orhydrate thereof, for use in therapy. In some embodiments the compound isa compound of Formula (I) or Formula (Ia) or pharmaceutically acceptablesalt, solvate or hydrate thereof. In some embodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe a compound according to any embodimentdescribed herein, or pharmaceutically acceptable salt, solvate orhydrate thereof, for use in the treatment or prevention of a conditionassociated with an AhR imbalance. In some embodiments the compound is acompound of Formula (I) or Formula (Ia), or pharmaceutically acceptablesalt, solvate or hydrate thereof. In some embodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe a compound according to any embodimentdescribed herein, or pharmaceutically acceptable salt, solvate orhydrate thereof, for use in the treatment or prevention of an AhRmediated disease. In some embodiments the compound is a compound ofFormula (I) or Formula (Ia), or pharmaceutically acceptable salt,solvate or hydrate thereof. In some embodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe a compound according to any embodimentdescribed herein, or pharmaceutically acceptable salt, solvate orhydrate thereof, for use in the treatment or prevention of aninflammatory disease or disorder. In some embodiments the compound is acompound of Formula (I) or Formula (Ia), or pharmaceutically acceptablesalt, solvate or hydrate thereof. In some embodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof

Some embodiments describe a compound according to any embodimentdescribed herein, or pharmaceutically acceptable salt, solvate orhydrate thereof, for use in the treatment or prevention of adermatological condition or disorder. In some embodiments the compoundis a compound of Formula (I) or Formula (Ia), or pharmaceuticallyacceptable salt, solvate or hydrate thereof. In some embodiments thecompound is 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or apharmaceutically acceptable salt, solvate or hydrate thereof.

Some embodiments describe a compound according to any embodimentdescribed herein, or pharmaceutically acceptable salt, solvate orhydrate thereof, for use in the treatment or prevention of psoriasis. Insome embodiments the compound is a compound of Formula (I) or Formula(Ia), or pharmaceutically acceptable salt, solvate or hydrate thereof.In some embodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe a compound according to any embodimentdescribed herein, or pharmaceutically acceptable salt, solvate orhydrate thereof, for use in the treatment or prevention of a atopicdermatitis. In some embodiments the compound is a compound of Formula(I) or Formula (Ia), or pharmaceutically acceptable salt, solvate orhydrate thereof. In some embodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe use of a compound according to any embodimentdescribed herein, or a pharmaceutically acceptable salt, solvate orhydrate thereof, in the manufacture of a medicament for a conditionassociated with an AhR imbalance. in a subject in need thereof. In someembodiments the compound is a compound of Formula (I) or Formula (Ia),or pharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe use of a compound according to any embodimentdescribed herein, or a pharmaceutically acceptable salt, solvate orhydrate thereof, in the manufacture of a medicament for the treatment ofan AhR mediated disease in a subject in need thereof. In someembodiments the compound is a compound of Formula (I) or Formula (Ia),or pharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe use of a compound according to any embodimentdescribed herein, or a pharmaceutically acceptable salt, solvate orhydrate thereof, in the manufacture of a medicament for the treatment orprevention of an inflammatory disorder in a subject in need thereof. Insome embodiments the compound is a compound of Formula (I) or Formula(Ia), or pharmaceutically acceptable salt, solvate or hydrate thereof.In some embodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe use of a compound according to any embodimentdescribed herein, or a pharmaceutically acceptable salt, solvate orhydrate thereof, in the manufacture of a medicament for the treatment orprevention of a dermatological condition or disorder in a subject inneed thereof. In some embodiments the compound is a compound of Formula(I) or Formula (Ia), or pharmaceutically acceptable salt, solvate orhydrate thereof. In some embodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof. Some embodiments describeuse of a compound according to any embodiment described herein, or apharmaceutically acceptable salt, solvate or hydrate thereof, in themanufacture of a medicament for the treatment or prevention of psoriasisin a subject in need thereof. In some embodiments the compound is acompound of Formula (I) or Formula (Ia), or pharmaceutically acceptablesalt, solvate or hydrate thereof. In some embodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe use of a compound according to any embodimentdescribed herein, or a pharmaceutically acceptable salt, solvate orhydrate thereof, in the manufacture of a medicament for the treatment orprevention of atopic dermatitis in a subject in need thereof. In someembodiments the compound is a compound of Formula (I) or Formula (Ia),or pharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe use of a compound according to any embodimentdescribed herein, or pharmaceutically acceptable salt, solvate orhydrate thereof, for the treatment or prevention of a conditionassociated with AhR imbalance in a subject in need thereof. In someembodiments the compound is a compound of Formula (I) or Formula (Ia),or pharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe use of a compound according to any embodimentdescribed herein, or pharmaceutically acceptable salt, solvate orhydrate thereof, for the treatment or prevention of AhR mediateddisease. In some embodiments the compound is a compound of Formula (I)or Formula (Ia), or pharmaceutically acceptable salt, solvate or hydratethereof. In some embodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe use of a compound according to any embodimentdescribed herein, or pharmaceutically acceptable salt, solvate orhydrate thereof, for the treatment or prevention of an inflammatorydisease or disorder. In some embodiments the compound is a compound ofFormula (I) or Formula (Ia), or pharmaceutically acceptable salt,solvate or hydrate thereof. In some embodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe use of a compound according to any embodimentdescribed herein, or pharmaceutically acceptable salt, solvate orhydrate thereof, in the manufacture of a medicament for the treatment orprevention of a dermatological condition or disorder. In someembodiments the compound is a compound of Formula (I) or Formula (Ia),or pharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe use of a compound according to any embodimentdescribed herein, or pharmaceutically acceptable salt, solvate orhydrate thereof, in the manufacture of a medicament for the treatment orprevention of psoriasis. In some embodiments the compound is a compoundof Formula (I) or Formula (Ia), or pharmaceutically acceptable salt,solvate or hydrate thereof. In some embodiments the compound is2-isopropyl-5-(isoquinolin yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Some embodiments describe use of a compound according to any embodimentdescribed herein, or pharmaceutically acceptable salt, solvate orhydrate thereof, in the manufacture of a medicament for the treatment orprevention of atopic dermatitis. In some embodiments the compound is acompound of Formula (I) or Formula (Ia), or pharmaceutically acceptablesalt, solvate or hydrate thereof. In some embodiments the compound is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

Combinations

For the pharmaceutical compositions and the methods/uses describedherein, a compound of any embodiment described herein, may beadministered in combination with one or more other therapies and/oractive agents. In some embodiments, the compound of any embodimentdescribed herein is administered in combination with a second agentindicated for the disorders or diseases described herein, eitherconcomitant with, prior to, or after the administration of the secondagent. In some embodiments the second agent is in the same formulationas a compound according to any embodiment described herein. In someembodiments, the second agent is in a separate formulation. The secondtherapeutic agent may be administered by the same route as the compoundaccording to any embodiment described herein, or it may be administeredby a different route than the compound according to any embodimentdescribed herein. For example, a compound according to any embodimentdescribed herein may be administered topically and the second agent maybe administered topical, orally, intravenously intramuscularly, otic,opthamologicaly, opthalmically, vaginally, rectally, etc. In someembodiments the second agent is administered concomitant with a compoundof the invention. In some embodiments the second agent is administeredprior to the compound of the invention. In some embodiments the secondagent is administered after the compound of the invention.

In other words, a compound according to any embodiment described herein,may be administered together, contemporaneously or sequentially ineither order to the site of administration, or to a desired site ofaction. The order of administration is not deemed necessary. However, iftopically administered it may be preferable that the two or more activesare in contact at some point together at the site of administration ordesired site of action. Alternatively, it is desirable that the timeperiod for appropriate mode of action of the actives is timedappropriately in the delivery time of the active. If both are present inthe same vehicle they provide ease of administration to the patient, andperhaps increased compliance, but it is not required for the inventionherein.

When a compound according to any embodiment described herein, isadministered in combination with one or more other therapies and/oractive agents as described herein, each of the active drug components(i.e. the compound of the present invention and the second agent) iscontained in an effective dosage amount.

In some embodiments, the second agent is an agent for treating orpreventing a condition associated with an AhR imbalance.

In some embodiments the other agent(s) is useful in the prevention ortreatment of allergic disease, inflammatory disease, or autoimmunedisease. In some embodiments the agent(s) is antigen immunotherapyagents; anti-histamines; corticosteroids, for example, fluticasonepropionate, fluticasone furoate, beclomethasone dipropionate,budesonide, ciclesonide, mometasonefuroate, triamcinolone, andflunisolide; NSAIDs; leukotriene modulators, such as montelukast,zafirlukast, and pranlukast; iNOS inhibitors; tryptase inhibitors; IKK2inhibitors; p38 inhibitors; Syk inhibitors; protease inhibitors;elastase inhibitors; integrin antagonists, for example, beta-2integrinantagonists; adenosine A2a agonists; mediator release inhibitors, forexample, sodium chromoglycate, 5-lipoxygenase inhibitors (zyflo); DP1antagonists; DP2 antagonists; PI3K delta inhibitors; ITK inhibitors; LP(lysophosphatidic) inhibitors; or FLAP (5-lipoxygenase activatingprotein) inhibitors, for example, sodium3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-((5-methylpyridin-2-yl)methoxy)-1H-indol-2-yl)-2,2-dimethylpropanoate);bronchodilators, for example, muscarinic antagonists and beta-2agonists; methotrexate, and similar agents; monoclonal antibody therapyagents such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12,anti-IL-1 and similar agents; cytokine receptor therapies, for examples,etanercept and similar agents; and antigen non-specific immunotherapies,for example, interferon or other cytokines/chemokines, chemokinereceptor modulators such as CCR3, CCR4 or CXCR2 antagonists, othercytokine/chemokine agonists or antagonists, TLR agonists and similaragents.

In some embodiments the other agent(s) is an agent for aidingtransplantation, including cyclosporines, tacrolimus, mycophenolatemofetil, prednisone, azathioprine, sirolimus, daclizumab, basiliximab,or OKT3.

In some embodiments the other agent(s) is an agent for treatingdiabetes, for example, metformin (biguanides), meglitinides,sulfonylureas, DPP-4 inhibitors, thiazolidinediones, oralpha-glucosidase inhibitors, amylin mimetics, incretin mimetics, orinsulin.

In some embodiments the other agent(s) is an antihypertensive such asdiuretics, ACE inhibitors, ARBS, calcium channel blockers, and betablockers.

Accordingly, the disclosure provides, in a further aspect, apharmaceutical composition comprising at least one compound according toany embodiment described herein, or pharmaceutically acceptablederivative thereof; a second active agent; and, optionally apharmaceutically acceptable carrier.

When combined in the same formulation it will be appreciated that thetwo or more compounds must be stable and compatible with each other andthe other components of the formulation. When formulated separately theymay be provided in any convenient formulation, in such manner as areknown for such compounds in the art.

Preservatives, stabilizers, dyes and flavoring agents may be provided inany pharmaceutical composition described herein. Examples ofpreservatives include sodium benzoate, ascorbic acid and esters ofp-hydroxybenzoic acid. Antioxidants and suspending agents may be alsoused.

With respect to combinations including biologics such as monoclonalantibodies or fragments, suitable excipients will be employed to preventaggregation and stabilize the antibody or fragment in solution with lowendotoxin, generally for parenteral administration, for example,intravenous, administration. For example, see Formulation and DeliveryIssues for Monoclonal Antibody Therapeutics, Daugherty et al., inCurrent Trends in Monoclonal Antibody Development and Manufacturing,Part 4, 2010, Springer, New York pp 103-129.

Routes of Administration and Unit Dosage Forms

Compounds according to any embodiment described herein andpharmaceutical compositions incorporating said compounds mayconveniently be administered by any of the routes conventionally usedfor drug administration, for instance, orally, topically, transdermally,parenterally or by inhalation. The compounds may be administered inconventional dosage forms prepared by combining a compound according toany embodiment described herein with standard pharmaceutical carriersaccording to conventional procedures. A compound according to anyembodiment described herein, may also be administered in conventionaldosages in combination with known, second therapeutically activecompounds as further described herein. These procedures may involvemixing, granulating and compressing or dissolving the ingredients asappropriate to the desired preparation. It will be appreciated that theform and character of the pharmaceutically acceptable character ordiluent is dictated by the amount of active ingredient with which it isto be combined, the route of administration and other well-knownvariables. The carrier(s) must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

A compound according to any embodiment described herein, may beadministered topically, that is by non-systemic administration. Thisincludes the application of the compound externally to the epidermis,the buccal cavity, or the instillation of such a compound into the ear,eye and nose, such that the compound does not significantly enter theblood stream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as liniments, lotions, creams, gels,solutions, ointments, pastes, and drops suitable for administration tothe skin, the eye, ear or nose.

Lotions according to the present invention include those suitable forapplication to the skin, ear, nose or eye. An eye lotion may comprise asterile aqueous solution optionally containing a bactericide and may beprepared by methods similar to those for the preparation of drops.Lotions or liniments for application to the skin may also include anagent to hasten drying and to cool the skin, such as an alcohol oracetone, and/or a moisturizer such as glycerol or an oil such as castoroil or arachis oil.

Creams, gels, ointments or pastes according to the present invention aresemi-solid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient (i.e., acompound according to any embodiment described herein) in finely-dividedor powdered form, alone or in solution or suspension in an aqueous ornon-aqueous fluid, with the aid of suitable machinery, with a greasy ornon-greasy base. The base may comprise hydrocarbons such as hard, softor liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; anoil of natural origin such as almond, corn, arachis, castor or oliveoil; wool fat or its derivatives or a fatty acid such as steric or oleicacid together with an alcohol such as propylene glycol or a macrogel.The formulation may incorporate any suitable surface active agent suchas an anionic, cationic or non-ionic surfactant such as a sorbitan esteror a polyoxyethylene derivative thereof. Suspending agents such asnatural gums, cellulose derivatives or inorganic materials such assilicaceous silicas, and other ingredients such as lanolin, may also beincluded.

Drops according to the present invention may comprise sterile aqueous oroily solutions or suspensions and may be prepared by dissolving theactive ingredient in a suitable aqueous solution of a bactericidaland/or fungicidal agent and/or any other suitable preservative, andpreferably including a surface active agent. The resulting solution maythen be clarified by filtration, transferred to a suitable containerwhich is then sealed and sterilized by autoclaving or maintaining at98-100° C. for half an hour. Alternatively, the solution may besterilized by filtration and transferred to the container by an aseptictechnique. Examples of bactericidal and fungicidal agents suitable forinclusion in the drops are phenyl mercuric nitrate or acetate (0.002%),benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).Suitable solvents for the preparation of an oily solution includeglycerol, diluted alcohol and propylene glycol.

In some embodiments, a compound according to any embodiment describedherein is administered topically in as a cream, gel ointment, paste,drop or lotion. In some embodiments a compound according to anyembodiment described herein is administered as a gel or cream. In someembodiments a compound according to any embodiment described herein isadministered as a gel. In some embodiments a compound according to anyembodiment described herein is administered as a cream.

In some embodiments, the pharmaceutical formulation comprises a compoundaccording to any embodiment described herein, and a pharmaceuticallyacceptable excipient or diluent and an anti-oxidant, preservative,gelling agent, pH adjusting agent, or stabilizer, or mixtures thereofsuitably adapted for topical administration to the skin, eye, or ear ofa patient.

In some embodiments the composition is a cream or gel composition andthe compound of Formula (I) is2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol.

In some embodiments the composition is a cream formulation. In someembodiments the composition is cream formulation 1 comprising thefollowing:

Composition Formulation Component (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 0-1 Propylene glycol15.0 Transcutol P 10.0 PEG400 20.0 Miglyol 810 5.0 PEG40 Stearate 1.0Glyceryl monostearate 1.5 Stearic acid 0.15 Cetostearyl alcohol 50 3.0Benzyl alcohol 1.0 BHT 0.1 Water QS 100

It will be understood that when the2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in cream formulation 1is present at a particular concentration (in the range of 0-1%), theformulation may be referred to as X % cream formulation 1. For example,in some embodiments the composition is a cream formulation 1, comprising1% of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (1% creamformulation 1). Thus, 1% cream formulation 1 comprises:

Composition Formulation Component (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 1 Propylene glycol 15.0Transcutol P 10.0 PEG400 20.0 Miglyol 810 5.0 PEG40 Stearate 1.0Glyceryl monostearate 1.5 Stearic acid 0.15 Cetostearyl alcohol 50 3.0Benzyl alcohol 1.0 BHT 0.1 Water QS 100

In some embodiments the composition is 0.5% cream formulation 1comprising

Composition Formulation Component (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 0.5 Propylene glycol15.0 Transcutol P 10.0 PEG400 20.0 Miglyol 810 5.0 PEG40 Stearate 1.0Glyceryl monostearate 1.5 Stearic acid 0.15 Cetostearyl alcohol 50 3.0Benzyl alcohol 1.0 BHT 0.1 Water QS 100

In some embodiments the composition is 0.1% cream formulation 1comprising

Composition Formulation Component (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 0.1 Propylene glycol15.0 Transcutol P 10.0 PEG400 20.0 Miglyol 810 5.0 PEG40 Stearate 1.0Glyceryl monostearate 1.5 Stearic acid 0.15 Cetostearyl alcohol 50 3.0Benzyl alcohol 1.0 BHT 0.1 Water QS 100

In some embodiments the composition is cream formulation 2 comprisingthe following:

Composition Formulation Component (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 0-1 Propylene glycol15.0 Transcutol P 15.0 PEG400 20.0 Miglyol 810 5.0 PEG40 Stearate 1.0Glyceryl monostearate 1.5 Stearic acid 0.15 Cetostearyl alcohol 50 3.0Benzyl alcohol 1.0 BHT 0.1 Water QS 100

In some embodiments the composition is cream formulation 3 comprisingthe following:

Composition Formulation Component (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 0-1 Propylene glycol35.0 Transcutol P 15.0 Miglyol 810 5.0 Steareth 21 5 Steareth 2Cetostearyl alcohol 50 3.0 Benzyl alcohol 1.0 BHT 0.1 Water QS 100

In some embodiments the composition is 1% cream formulation 3 comprising

Composition Formulation Component (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 1 Propylene glycol 35.0Transcutol P 15.0 Miglyol 810 5.0 Steareth 21 5 Steareth 2 Cetostearylalcohol 50 3.0 Benzyl alcohol 1.0 BHT 0.1 Water QS 100

In some embodiments the composition is 0.5% cream formulation 3comprising

Composition Formulation Component (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 0.5 Propylene glycol35.0 Transcutol P 15.0 Miglyol 810 5.0 Steareth 21 5 Steareth 2Cetostearyl alcohol 50 3.0 Benzyl alcohol 1.0 BHT 0.1 Water QS 100

In some embodiments the composition is cream formulation 4 comprisingthe following:

Composition Formulation Component (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 0-1 Propylene glycol15.0 Transcutol P 25.0 Miglyol 810 5.0 Steareth 21 5 Steareth 2Cetostearyl alcohol 50 3.0 Benzyl alcohol 1.0 BHT 0.1 Carbomer p980 0.25Triethanolamine 0.2 Water QS 100

In some embodiments the composition is cream formulation 5 comprisingthe following:

Composition Formulation Component (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 0-1 Propylene glycol15.0 Transcutol P 25.0 Miglyol 810 5.0 Steareth 21 5 Steareth 2Cetostearyl alcohol 50 3.0 Benzyl alcohol 1.0 BHT 0.1 Xanthan gum 0.75Water QS 100

In some embodiments the composition is cream formulation 6 comprisingthe following:

Composition Formulation Component (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 0-1 Propylene glycol15.0 Transcutol P 25.0 Miglyol 810 5.0 Steareth 21 5 Steareth 2Cetostearyl alcohol 50 3.0 Benzyl alcohol 1.0 BHT 0.1 Xanthan gum 0.15Water QS 100

In some embodiments the composition is cream formulation 7 comprisingthe following:

Composition Formulation Component (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 0-1 Propylene glycol15.0 Transcutol P 25.0 Miglyol 810 5.0 Steareth 21 5 Steareth 2Cetostearyl alcohol 50 3.0 Benzyl alcohol 1.0 BHT 0.1 Water QS 100

In some embodiments the composition is a gel formulation (gelformulation 1) comprising the following:

Composition Formulation Component (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 0-1 Propylene glycol10.0 Transcutol P 35.0 Benzyl alcohol 2.0 BHT 0.05 Carbomer p980 0.5Trolamine 0.15 Water QS 100

In some embodiments the composition is a gel formulation (1% gelformulation 1) comprising the following:

Composition Formulation Component (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 1 Propylene glycol 10.0Transcutol P 35.0 Benzyl alcohol 2.0 BHT 0.05 Carbomer p980 0.5Trolamine 0.15 Water QS 100

In some embodiments the composition is a gel formulation (gelformulation 2) comprising the following:

Composition Formulation Component (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 0-1 Transcutol P 35.0PEG400 10.0 Benzyl alcohol 2.0 BHT 0.05 Carbomer p980 0.5 Trolamine 0.2Water QS 100

In some embodiments the composition is a gel formulation (gelformulation 3) comprising the following:

Formulation Component Composition (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 0-1 Propylene glycol20.0 Transcutol P 25.0 Benzyl alcohol 2.0 BHT 0.05 Carbomer p980 0.5Trolamine 0.15 Water QS 100

In some embodiments the composition is a gel formulation (gelformulation 4) comprising the following:

Formulation Component Composition (% w/w)2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 0-1 Propylene glycol40.0 Transcutol P 15.0 Benzyl alcohol 2.0 BHT 0.05 Carbomer p980 0.5Trolamine 0.15 Water QS 100

While topical usage is a preferred administration route, a compoundsaccording to any embodiment described herein, may also be administeredparenterally, that is by intravenous, intramuscular, subcutaneous,intranasal, intrarectal, intravaginal or intraperitoneal administration.The subcutaneous and intramuscular forms of parenteral administrationare generally preferred. Appropriate dosage forms for suchadministration may be prepared by conventional techniques. A compoundaccording to any embodiment described herein, may also be administeredby inhalation, that is by intranasal and oral inhalation administration.Appropriate dosage forms for such administration, such as an aerosolformulation or a metered dose inhaler, may be prepared by conventionaltechniques.

The dosage of a compound according to any embodiment described herein,as an active ingredient of this invention may be varied so that asuitable dosage form is obtained. The active ingredient may beadministered to subjects (animals and human) in need of such treatmentin dosages that will provide optimal pharmaceutical efficacy. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from patient to patient depending upon the nature and severityof disease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize.

In some embodiments, the amount of the compound to be administered canrange between about 0.1 and about 100 mg/kg/day. Generally, dosagelevels of between 0.1 to 10 mg/kg of body weight daily are administeredto the patient, e.g., humans. In some embodiments the therapeuticallyeffective amount is between a lower limit of about 0.1 mg/kg of bodyweight, about 0.2 mg/kg of body weight, about 0.3 mg/kg of body weight,about 0.4 mg/kg of body weight, about 0.5 mg/kg of body weight, about0.6 mg/kg of body weight, about 0.7 mg/kg of body weight, about 0.8mg/kg of body weight, about 0.9 mg/kg of body weight, about 1 mg/kg ofbody weight, about 5 mg/kg of body weight, about 10 mg/kg of bodyweight, about 15 mg/kg of body weight, about 20 mg/kg of body weight,about 25 mg/kg of body weight, about 30 mg/kg of body weight, about 35mg/kg of body weight, about 40 mg/kg of body weight, about 45 mg/kg ofbody weight, about 50 mg/kg of body weight, 55 mg/kg of body weight,about 60 mg/kg of body weight, about 65 mg/kg of body weight, about 70mg/kg of body weight, about 75 mg/kg of body weight, about 80 mg/kg ofbody weight, about 85 mg/kg of body weight, about 80 mg/kg of bodyweight, about 95 mg/kg of body weight, and about 100 mg/kg of bodyweight; and an upper limit of 100 mg/kg of body weight, about 95 mg/kgof body weight, about 90 mg/kg of body weight, about 85 mg/kg of bodyweight, about 80 mg/kg of body weight, about 75 mg/kg of body weight,about 70 mg/kg of body weight, about 65 mg/kg of body weight, about 60mg/kg of body weight, about 55 mg/kg of body weight 50 mg/kg of bodyweight, about 45 mg/kg of body weight, about 40 mg/kg of body weight,about 35 mg/kg of body weight, about 30 mg/kg of body weight, about 25mg/kg of body weight, about 20 mg/kg of body weight, about 15 mg/kg ofbody weight, about 10 mg/kg of body weight, about 5 mg/kg of bodyweight, about 1 mg/kg of body weight, about 0.9 mg/kg of body weight,about 0.8 mg/kg of body weight, about 0.7 mg/kg of body weight, about0.6 mg/kg of body weight, about 0.5 mg/kg of body weight, about 0.4mg/kg of body weight, about 0.3 mg/kg of body weight, about 0.2 mg/kg ofbody weight, and about 0.1 mg/kg of body weight per day.

In some embodiments, a compound according to any embodiment describedherein is administered to a subject at a total daily dose of about 0.01to about 1000 mg/day. In some embodiments the total daily dose is about0.1 to about 100 mg/day. In some embodiments the total daily dose isbetween a lower limit of about 0.01 mg/ day, about 0.05 mg/day, 0.1mg/day, about 0.5 mg/day, about 1 mg/day, about 10 mg/day, about 20mg/day, about 30 mg/day, about 40 mg/day, about 50 mg/day, about 60mg/day, about 70 mg/day, about 80 mg/day, about 90 mg/day, about 100mg/day, about 110 mg/day, about 120 mg/day, about 130 mg/day, about 140mg/day, about 150 mg/day, about 160 mg/day, about 170 mg/day, about 180mg/day, about 190 mg/day, about 200 mg/day, about 210 mg/day, about 220mg/day, about 230 mg/day, about 240 mg/day, about 250 mg/day, about 260mg/day, about 270 mg/day, about 280 mg/day, about 290 mg/day, about 300mg/day, about 310 mg/day, about 320 mg/day, about 330 mg/day, about 340mg/day, about 350 mg/day, about 360 mg/day, about 370 mg/day, about 380mg/day, about 390 mg/day, about 400 mg/day, about 410 mg/day, about 420mg/day, about 430 mg/day, about 440 mg/day, about 450 mg/day, about 460mg/day, about 470 mg/day, about 480 mg/day, about 490 mg/day, about 500mg/day, about 510 mg/day, about 520 mg/day, about 530 mg/day, about 540mg/day, about 550 mg/day, about 560 mg/day, about 570 mg/day, about 580mg/day, about 590 mg/day, about 600 mg/day, about 610 mg/day, about 620mg/day, about 630 mg/day, about 640 mg/day, about 650 mg/day, about 660mg/day, about 670 mg/day, about 680 mg/day, about 690 mg/day, about 700mg/day, about 710 mg/day, about 720 mg/day, about 730 mg/day, about 740mg/day, about 750 mg/day, about 760 mg/day, about 770 mg/day, about 780mg/day, about 790 mg/day, about 800 mg/day, about 810 mg/day, about 820mg/day, about 830 mg/day, about 840 mg/day, about 850 mg/day, about 860mg/day, about 870 mg/day, about 880 mg/day, about 890 mg/day, about 900mg/day, about 910 mg/day, about 920 mg/day, about 930 mg/day, about 940mg/day, about 950 mg/day, about 960 mg/day, about 970 mg/day, about 980mg/day, about 990 mg/day, and about 1000 mg/day, and an upper limit of1000 mg/day, about 990 mg/day, about 980 mg/day, about 970 mg/day, about960 mg/day, about 950 mg/day, about 940 mg/day, about 930 mg/day, about920 mg/day, about 910 mg/day, about 900 mg/day, about 890 mg/day, about880 mg/day, about 870 mg/day, about 860 mg/day, about 850 mg/day, about840 mg/day, about 830 mg/day, about 820 mg/day, about 810 mg/day, about800 mg/day, about 790 mg/day, about 780 mg/day, about 770 mg/day, about760 mg/day, about 750 mg/day, about 740 mg/day, about 730 mg/day, about720 mg/day, about 710 mg/day, about 700 mg/day, about 690 mg/day, about680 mg/day, about 670 mg/day, about 660 mg/day, about 650 mg/day, about640 mg/day, about 630 mg/day, about 620 mg/day, about 610 mg/day, about600 mg/day, about 590 mg/day, about 580 mg/day, about 570 mg/day, about560 mg/day, about 550 mg/day, about 540 mg/day, about 530 mg/day, about520 mg/day, about 510 mg/day, about 500 mg/day, about 490 mg/day, about480 mg/day, about 470 mg/day, about 460 mg/day, about 450 mg/day, about440 mg/day, about 430 mg/day, about 420 mg/day, about 410 mg/day, about400 mg/day, about 390 mg/day, about 380 mg/day, about 370 mg/day, about360 mg/day, about 350 mg/day, about 340 mg/day, about 330 mg/day, about320 mg/day, about 310 mg/day, about 300 mg/day, about 290 mg/day, about280 mg/day, about 270 mg/day, about 260 mg/day, about 250 mg/day, about240 mg/day, about 230 mg/day, about 220 mg/day, about 210 mg/day, about200 mg/day, about 190 mg/day, about 180 mg/day, about 170 mg/day, about160 mg/day, about 150 mg/day, about 140 mg/day, about 130 mg/day, about120 mg/day, about 110 mg/day, about 100 mg/day, about 90 mg/day, about80 mg/day, about 70 mg/day, about 60 mg/day, about 50 mg/day, about 40mg/day, about 30 mg/day, about 10 mg/day, about 1 mg/day, about 0.5mg/day, about 0.1 mg/day, and about 0.01 mg/day.

It will be understood that the pharmaceutical compositions of thedisclosure need not necessarily contain the entire amount of thecompound that is effective in treating the disorder, as such effectiveamounts can be reached by administration of a plurality of divided dosesof such pharmaceutical compositions. The compounds may be administeredin a single dose per day or on a regimen of multiple doses per day,(e.g. two, three, four, five, or more) of sub-doses per day such thatthe total daily dose is the same. An effective amount of a salt thereofmay be determined as a proportion of the effective amount of thecompound of according to any embodiment described herein. Similardosages should be appropriate for treatment of the other conditionsreferred herein for treatment. In general, determination of appropriatedosing can be readily arrived at by one skilled in medicine or thepharmaceutical arts.

The active ingredient, i.e., a compound according to any embodimentdescribed herein, may be for topical administration administered fromabout 0.001% w/w to about 10% w/w of the topical formulation. In someembodiments, a compound according to any embodiment described herein is0.1% w/w, 0.2% w/w, 0.3% w/w, 0.4% w/w, 0.5% w/w, 0.6% w/w, 0.7% w/w,0.8% w/w, 0.9% w/w, 1% w/w, 2% w/w, 3% w/w, 4% w/w, 5% w/w, 6% w/w, 7%w/w, 8% w/w, 9% w/w, or 10% w/w of the topical formulation. In someembodiments a compound according to any embodiment described herein isfrom 1% w/w to 2% w/w of the formulation. The daily topical dosageregimen may be from about 0.1 mg to 150 mg of a compound according toany embodiment described herein, administered one to four times daily.In some embodiments the daily topical dose is 0.1 mg, 0.2 mg, 0.3 mg,0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg,5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg,16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg,106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg,115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg,124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg,133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg,142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, or 150mg. Initial dosages can also be estimated from in vivo data, usinganimal models. Animal models useful for testing the efficacy ofcompounds to treat or prevent the various diseases described above arewell-known in the art. The compounds may be administered once per week,several times per week (for example, every other day), once per day ormultiple times per day, depending upon the judgment of the prescribingphysician.

It will also be recognized by one of skill in the art that the optimalquantity and spacing of individual dosages of a compound according toany embodiment described herein, or a pharmaceutically acceptable salt,solvate or hydrate thereof will be determined by the nature and extentof the condition being treated, the form, route and site ofadministration, and the patient being treated, and that such optimumscan be determined by conventional techniques. It will also beappreciated by one of skill in the art that the optimal course oftreatment, i.e., the number of doses of a compound according to anyembodiment described herein or a pharmaceutically acceptable salt,solvate or hydrate thereof, given per day for a defined number of days,can be ascertained by those skilled in the art using conventional courseof treatment determination tests.

Process for Preparing The Compound of Formula 8

Some embodiments describe a process for preparing compound of Formula 8

or a pharmaceutically acceptable salt, solvate or hydrate thereof,comprising demethylating a compound of Formula 7

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In some embodiments the process further comprises coupling a compound ofFormula 6

or a pharmaceutically acceptable salt, solvate or hydrate thereof with acompound of Formula 5

or a pharmaceutically acceptable salt, solvate or hydrate thereof toform the compound of Formula 7.

In some embodiments the process further comprises borylating a compoundof Formula 4

or a pharmaceutically acceptable salt, solvate or hydrate thereof toform the compound of Formula 5.

In some embodiments the process further comprises hydrogenating acompound of Formula 3

or a pharmaceutically acceptable salt, solvate or hydrate thereof toform the compound of Formula 4.

In some embodiments the process further comprises treating a ketone ofFormula 2

or a pharmaceutically acceptable salt, solvate or hydrate thereof with aGrignard reagent, followed by elimination of water under acidicconditions to form the compound of Formula 3.

In some embodiments the process further comprises alkylating2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvateor hydrate thereof, to form the compound of Formula 2.

In some embodiments the demethylation of the compound of Formula 7 toform the compound of Formula 8 comprises treating the compound ofFormula 7 with boron tribromide.

In some embodiments the demethylation of the compound of Formula 7 toform the compound of Formula 8 comprises: a) treating the compound ofFormula 7 with boron tribromide to form the compound of Formula 7-1

and b) hydrogenating the compound of Formula 7-1 to form the compound ofFormula 8.

In some embodiments the demethylation of the compound of Formula 7 toform the compound of Formula 8 comprises treating the compound ofFormula 7 with hydrobromic acid.

Some embodiments describe a process for preparing a compound of Formula8

-   -   comprising:    -   a) coupling a compound of Formula 6

-   -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof with the compound of Formula 5 or a pharmaceutically        acceptable salt, solvate or hydrate thereof to form a compound        of Formula 7

-   -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof; and    -   b) demethylating the compound of Formula 7 to form the compound        of Formula 8.    -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof

In some embodiments the compound of Formula 6

or a pharmaceutically acceptable salt, solvate or hydrate thereofaccording to any process described herein, is prepared by treatingisoquinoline-3-ol with a triflating agent.

In some embodiments the compound of Formula 5 or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, according to any processdescribed herein, is prepared by a process comprising:

-   -   a) alkylating 2,6-dihydroxyacetophenone or a pharmaceutically        acceptable salt, solvate or hydrate thereof, to form a compound        of Formula 2

-   -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof;    -   b) treating the ketone of Formula 2 or a pharmaceutically        acceptable salt, solvate or hydrate thereof with a Grignard        reagent, followed by elimination of water under acidic        conditions to form a compound of Formula 3

-   -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof;    -   c) hydrogenating the compound of Formula 3 or a pharmaceutically        acceptable salt, solvate or hydrate thereof to form a compound        of Formula 4

-   -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof; and    -   d) borylating the compound of Formula 4 or a pharmaceutically        acceptable salt, solvate or hydrate thereof to form a compound        of Formula 5 or a pharmaceutically acceptable salt, solvate or        hydrate thereof.

Some embodiments describe a process for preparing a compound of Formula8

-   -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof, comprising:    -   a) preparing a compound of Formula 5

-   -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof, comprising        -   1) alkylating 2,6-dihydroxyacetophenone or a            pharmaceutically acceptable salt, solvate or hydrate thereof            to form a comnound of Formula 2

-   -    or a pharmaceutically acceptable salt, solvate or hydrate        thereof;        -   2) treating the ketone of Formula 2 or a pharmaceutically            acceptable salt, solvate or hydrate thereof with a Grignard            reagent, followed by elimination of water under acidic            conditions to form a compound of Formula 3

-   -    or a pharmaceutically acceptable salt, solvate or hydrate        thereof;        -   3) hydrogenating the compound of Formula 3 or a            pharmaceutically acceptable salt, solvate or hydrate thereof            to form a compound of Formula 4

-   -    or a pharmaceutically acceptable salt, solvate or hydrate        thereof; and        -   4) borylating the compound of Formula 4 or a            pharmaceutically acceptable salt, solvate or hydrate thereof            to form the compound of Formula 5 or a pharmaceutically            acceptable salt, solvate or hydrate thereof;    -   b) preparing a compound of Formula 6

-   -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof comprising treating isoquinoline-3-ol with a triflating        agent; and    -   c) coupling the compound of Formula 6 or a pharmaceutically        acceptable salt, solvate or hydrate thereof with the compound of        Formula 5 or a pharmaceutically acceptable salt, solvate or        hydrate thereof to form a compound of Formula 7

-   -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof; and    -   d) demethylating the compound of Formula 7 to form the compound        of Formula 8. or a pharmaceutically acceptable salt, solvate or        hydrate thereof; wherein steps a and b can be done in either        order or simultaneously in different reaction vessels.

In some embodiments according to any process described herein, theprocess further comprises purifying the compound of Formula 8. In someembodiments the purifying comprises crystallizing the compound ofFormula 8.

Appropriate amounts in any given instance will be readily apparent tothose skilled in the art or capable of determination by routineexperimentation. The compositions are generally applied in topicalmanner to the affected area, i. e., localized application to the skinregion where the clinical abnormality is manifest.

Unless otherwise indicated, all percentages are based on the percent byweight of the final composition prepared, and all totals equal 100% byweight.

EXAMPLES

Although the present invention has been described in considerable detailwith reference to certain preferred embodiments thereof, other versionsare possible. Therefore, the spirit and scope of the appended claimsshould not be limited to the description and the preferred versionscontained within this specification. Various embodiments of the presentinvention will be illustrated with reference to the followingnon-limiting examples. The following examples are for illustrativepurposes only and are not to be construed as limiting the invention inany manner.

In the experimental descriptions, the following abbreviations may beused:

Abbreviation Meaning ACN Acetonitrile BBr₃ Boron tribromide Brinesaturated aqueous sodium chloride DCM or CH₂Cl₂ methylene chloride DMFN,N-dimethylformamide DMSO Dimethylsulfoxide EtOAc ethyl acetate H or hrHour HOAc Acetic acid HPLC High performance liquid chromatography LLiter LC liquid chromatography LCMS liquid chromatography-massspectroscopy MeOH Methanol MeOD Tetradeuteromethanol mL Milliliter MSmass spectroscopy Na₂SO₄ Sodium sulfate NMR Nuclear magnetic resonancespectroscopy PdCl₂(dppf)(1,1′-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride SGCCsilica gel column chromatography RT or rt Room temperature TEATriethylamine TFA trifluoroacetic acid TLC thin layer chromatographyt_(R) Retention time

LCMS Standard Method A

LC Conditions:

-   -   The UPLC analysis was conducted on a Waters Acquity BEH C18 2×50        mm 1.7 m column at 50° C.    -   0.5 uL of sample was injected using a partial loop (with needle        overfill) injection mode.    -   The gradient employed was:    -   Mobile Phase A: Water+0.20% v/v Formic Acid    -   Mobile Phase B: Acetonitrile+0.15% v/v Formic Acid    -   Time % A % B Flow Rate    -   min 95 5 1 ml/min    -   1.10 min 1 99 1 ml/min    -   1.50 min 1 99 1 ml/min    -   UV detection provided by summed absorbance signal from 210 to        350 nm scanning at 40 Hz.    -   MS Conditions:    -   Instrument: Waters Acquity    -   Serial Number: C07SQD043W    -   Scan Mode: Alternating Positive/Negative Electrospray    -   Scan Range: 125-1000 amu    -   Scan Time: 105 msec    -   Interscan Delay: 20 msec    -   Other Information    -   All equipment supplied by Waters Corp, Milford, Mass.    -   Quality control samples are run and analyzed minimally once per        day

LCMS Standard Method B

-   -   Mobile Phase: A: Water (0.01% TFA) B: ACN (0.01% TFA)    -   Gradient: 5% B increase to 95% B within 1.5 min,    -   95% B for 1.8 min, back to 5% B within 0.01 min    -   Flow Rate: 2.0 ml/min    -   Column: SunFire C18, 4.6×50 mm, 3.5 μm    -   Column Temperature: 50° C.    -   Detection: UV (280, 140 nm) and MS (ESI, Pos mode, 110 to 1000        amu)

LCMS Standard Method C

-   -   Mobile Phase: A: Water (10mM NH₄HCO₃) B: ACN    -   Gradient: 5% B increase to 95% B within 2 min,    -   95% B for 1.3 min, back to 5% B within 0.01 min    -   Flow Rate: 1.8 ml/min    -   Column: XBridge C18, 4.6×50 mm, 3.5 μm    -   Column Temperature: 40° C.    -   Detection: UV (280, 140 nm) and MS (ESI, Pos mode, 110 to 1000        amu)

Synthetic Examples

The skilled artisan will appreciate that if a substituent describedherein is not compatible with the synthetic methods described herein,the substituent may be protected with a suitable protecting group thatis stable to the reaction conditions. The protecting group may beremoved at a suitable point in the reaction sequence to provide adesired intermediate or target compound. Suitable protecting groups andthe methods for protecting and de-protecting different substituentsusing such suitable protecting groups are well known to those skilled inthe art. In some instances, a substituent may be specifically selectedto be reactive under the reaction conditions used. Under thesecircumstances, the reaction conditions convert the selected substituentinto another substituent that is either useful as an intermediatecompound or is a desired substituent in a target compound.

The synthesis of the compounds of the general formula as noted in thescheme(s) below and their pharmaceutically acceptable salts, solvates orhydrates thereof may be accomplished as outlined.

Abbreviations are as defined in the Examples section. Starting materialsare commercially available or are made from commercially availablestarting materials using methods known to those skilled in the art. Alltemperatures are given in degrees centigrade, all solvents are highestavailable purity and all reactions run under anhydrous conditions in anargon atmosphere unless otherwise indicated.

The compounds herein may be obtained by using synthetic proceduresillustrated in the Scheme below or by drawing on the knowledge of askilled organic chemist. The synthesis provided in this Scheme isapplicable for producing compounds of the invention having a variety ofdifferent substituent groups employing appropriate precursors, which aresuitably protected if needed, to achieve compatibility with thereactions outlined herein. Subsequent deprotection, where needed,affords compounds of the nature generally disclosed. While the scheme isshown with compounds only of Formula (I), it is illustrative ofprocesses that may be used to make the compounds of the invention.

Intermediates (compounds used in the preparation of the compounds of theinvention) may also be present as salts, solvates or hydrates. Thus, inreference to intermediates, the phrase “compound(s) of formula (number)”means a compound having that structural formula or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.

The invention also includes various deuterated forms of the compounds ofFormula (I). Each available hydrogen atom attached to a carbon atom maybe independently replaced with a deuterium atom. In some embodiments,one or more hydrogen atoms of a compound according to any embodimentdescribed herein, is replaced with a deuterium. A person of ordinaryskill in the art will know how to synthesize deuterated forms of thecompounds of Formula (I).

As further described herein for the schemes, there is a general formula(I)

wherein R¹-R⁶ are as defined previously for Formula (I).

General scheme:

The compounds of Formula (I) may be prepared by a carbon-carbonformation, such as transition metal catalyzed cross-coupling. Thereaction may be fulfilled by Suzuki-Miyaura coupling in the presence ofa catalyst, such as a Pd(0), Ni(0), Pd(II), or Ni(II) complex with aligand, including, but not limited to, PdCl₂(dppf), Pd(PPh₄)₄, Pd(OAc)₂,Pd₂(dba)₃, NiCl₂(dppf), and NiCl₂(PCy₃)₂, between an organoboronic acid,or boronate ester or potassium trifluoroborate and a halide or apseudohalide, such as a triflate. Such coupling reaction are carried outin the presence of a mild base, such as K₂CO₃, and Na₂CO₃, NaHCO₃,Cs₂CO₃, K₃PO₄, KF, etc., in a suitable solvent, such as toluene,dioxane, tetrahydrofuran, dimethoxyethane, and dimethylformamide, etc.Selection of suitable bases, ligands, solvents, and reaction conditions,for example, time, temperature, pressure, choice of atmosphere (forexample, inert), reaction work up, purification etc. are known to thoseof skill in the art.

One aspect of the invention is a process for making a compound ofFormula (I). The final compounds of Formula (I) may be prepared byde-protection from its precursor if any protecting groups are employedduring transformation. Suitable hydroxyl-protecting groups well known tothose skilled in the art can be found in Greene (vide supra). One suchexample of demethylation can be by use of boron tribromide in a suitableorganic solvent, such as methylene chloride, at −78° C. to +20° C.,preferably about −20° C. to 0° C. for about 0.5-72 hours. The progressof the reaction is monitored by thin layer chromatography or highpressure liquid chromatography. When the reaction is complete, it isquenched slowly with a suitable solvent, such as methyl alcohol at −78°C. to +20° C., preferably −20° C. to 10° C., and continued stirring atroom temperature for about 1-4 hours. Adding water afterwards isoptional. The excess solvent is removed by distillation. The residueobtained herein is purified by typical chromatography, normal phase orreverse phase, and recrystallization in suitable solvents.

The compounds of Formula (I) may be obtained from a precursor of Formula(I), such as Formula (A) described herein, by hydrogenation in thepresence of a suitable catalyst, such as 5 or 10% palladium on carbon,under hydrogen atmosphere at ambient temperature in a suitable organicsolvent, such as methanol, ethanol, isopropanol, ethyl acetate,tetrahydrofuran, etc.

General intermediate 1: 3,5-Diacetoxy-4-isopropylbenzoic acid

Step 1. 3,5-Dihydroxy-4-isopropylbenzoic Acid Triethylamine Salt

3,5-Dihydroxybenzoic acid (40 g, 0.26 mol, 1.0 equiv.) was charged to 1L three-neck round bottom flask (RBF) followed by concentrated sulfuricacid (160 mL, 4 volumes) at room temperature. Water (20 mL, 0.5 volumes)was charged to the mixture while stirring. The suspension was heated to60-65° C., then 2-propanol (25.0 mL, 0.32 mol, 1.25 equiv.) was chargedto the reaction drop wise over the period of ˜10 minutes. The clearreaction mixture was stirred at 60-65° C. for 4-8 hrs and cooled to roomtemperature (˜20° C.). The reaction mixture was transferred slowly intoan aqueous sodium hydroxide solution at 10° C. in a 2^(nd) 3 Lthree-neck round bottom flask (RBF) equipped with overhead stirrer. Theaqueous sodium hydroxide solution temperature was maintained in 2^(nd)RBF between 10-30° C. The reaction mixture flask was rinsed with waterto complete transferring, charged with tent-butyl methyl ether (TBME,320 mL, 8 volumes), warmed to 20-25° C. and stirred ˜30 min. The twolayers were separated and the aqueous layer was extracted with TBME(2×160 mL, 4 volumes). Potassium sodium tartrate solution was charged(1N, 160 mL, 4 volumes) to the combined TBME layers and stirred at leastfor 40 min. at 20-25° C. The two layers were separated, the organiclayer was passed through activated carbon Darco G-60, -100 mesh and thecarbon cake was washed with TBME. 2-Propanol (90 mL, 2.25 volumes) wascharged to the TBME layers, then triethylamine (36.2 mL, 1.0 equiv.) wascharged to the mixture (solution of TBME layers+2-propanol) drop-wiseover a period of ˜15 min at 20-25° C. and stirred at least 2.5 h. Theproduct was isolated by filtration and the cake was rinsed with TBME.The title product was dried in the oven overnight at 40-50° C. Purity byHPLC: 98%.

Step 2. 3,5-Diacetoxy-4-isopropylbenzoic Acid

3,5-Dihydroxy-4-isopropylbenzoic acid triethylamine salt (50.0 g, 0.17mol, 1.0 equiv.) was charged to a 1 L three-neck round bottom flask(RBF) followed by tent-butyl methyl ether (TBME, 250 mL), and 2-methyltetrahydrofuran (2Me-THF, 125 mL) at room temperature. Acetic anhydride(38.1 mL, 0.4 mol, 2.4 equiv.) and triethylamine (46.9 mL, 0.34 mol, 2.0equiv.) were charged to the mixture while stirring. The suspension washeated to 60-65° C. and stirred for 6-20 hrs or until the reaction wasdeemed complete by 3 min Fast LC. The mixture was cooled to roomtemperature (˜20 ° C.), and charged with 6N hydrochloric acid (6N HCl,175 mL) slowly while maintaining the reaction mixture temperaturebetween 20-30° C. and stirred at least 15 min. The two layers wereseparated, the organic layer was washed with water (100 mL) andevaporated at reduced pressure until ˜3.0 volumes were left in theflask. Toluene (200 mL) was added, and evaporated until ˜2 volumes wereleft in the flask. Toluene (75 mL) was added, the mixture was heated to75-80° C. and stirred at least 30 min. The product suspension was cooledto room temperature (˜20° C.), charged with cyclohexane (200 mL) andstirred at least 3 hrs at 15-20 ° C. The product was isolated byfiltration and the cake was rinsed with cyclohexane. The title productwas dried in the oven overnight at 40-50° C. ¹H NMR (400 MHz, DMSO-d₆) δppm 13.07-13.40 (br. s, 1 H), 7.54 (s, 2 H), 3.07-3.23 (Sep., 1 H), 2.35(s, 6 H), 1.18 (d, J=7 Hz, 6 H); Purity by HPLC: 97%.

General intermediate 2:2-(4-Isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared according to a method reported in theliterature (Xuebin Liao, Levi M. Stanley and John F. Hartwig, J. Am.Chem. Soc. 2011, 133, 2088-2091).

General intermediate 3: 5-bromo-2-(tert-butyl)phenol

The title compound was prepared by a method reported in the U.S. Pat.No. 5,919,970.

General intermediate 4: 4-cyclopentyl-3,5-bis(methoxymethoxy)phenyltrifluoromethanesulfonate

Step 1

To a stirred solution of 4-bromo-3,5-dihydroxybenzoic acid (4.06 g,17.42 mmol and N,N-diisopropylethylamine (17.65 mL, 101 mmol) in DCM(45.9 mL) at 0° C. was added methoxymethyl chloride (5.96 mL, 78 mmol).The reaction mixture was allowed to warm to rt and stirred for 30 minand then was quenched with saturated aqueous ammonium chloride (40 mL).The organic layer was separated, and the aqueous layer was extractedwith dichloromethane (3×40 mL). The combined organic extracts were driedover sodium sulfate, filtered, and concentrated. The residue waspurified using a 80 gram Isco brand silica column and eluted with10-100% EtOAc/Heptane (60 mL/min) to afford the desired compound as acolorless amorphous solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.54 (s,2 H), 5.50 (s, 2 H), 5.33 (s, 4 H), 3.57 (s, 3 H), 3.55 (s, 6 H); LCMSMethod A: t_(R)=0.84 min, 92%; MS (ESI): m/z no clear mass.

Step 2

To a stirred solution of methoxymethyl4-bromo-3,5-bis(methoxymethoxy)benzoate (1.055 g, 2.89 mmol) indichloromethane (DCM, 20.64 mL) at −78° C. was added DIBAL-H (1M inhexane, 8.67 mL, 8.67 mmol). The reaction mixture was warmed to 0° C.,stirred for 30 min and then iteratively quenched with EtOAc (1 mL) andthen MeOH (4 mL). Saturated aqueous potassium sodium tartrate (40 mL)was added and the resultant mixture was stirred vigorously overnight.The layers were separated and the aqueous layer was extracted withdichloromethane (3×50 mL). The combined organic extracts were dried oversodium sulfate, filtered, and concentrated. The residue was purifiedusing a 24 gram Isco brand silica column and eluted with 10-100%EtOAc/Heptane (35 mL/min) to yield the desired product as a colorlessoil. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.87 (s, 2 H), 5.28 (s, 4 H),4.66 (s, 2 H), 3.54 (s, 6 H); LCMS Method A: t_(R)=0.64 min, 94%; MS(ESI): m/z no clear mass.

Step 3

A solution of (4-bromo-3,5-bis(methoxymethoxy)phenyl)methanol (490 mg,1.595 mmol) and manganese dioxide (1387 mg, 15.95 mmol) indichloromethane (DCM, 31.908 mL) was stirred at rt for 12 h. The mixturewas diluted with diethyl ether, filtered through a pad of CELITE, andwashed with diethyl ether. The filtrate was concentrated, yielding thedesired compound pure product as a colorless amorphous solid. LCMSMethod A: t_(R)=0.78 min, 100%; MS (ESI): m/z 307.35 (M+2)⁺

Step 4

A sealed tube was charged with4-bromo-3,5-bis(methoxymethoxy)benzaldehyde (322 mg, 1.055 mmol),2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (320 μl,1.583 mmol), 1N sodium bicarbonate (3590 μl), 1,4-dioxane (8974 μl), andtetrakis(triphenylphosphine)palladium(0) (51.7 mg, 0.045 mmol). Thereaction mixture was heated at 100° C. overnight, cooled and partitionedbetween EtOAc and water. The organic phase was separated and the aqueouslayer was extracted with EtOAc. The combined organic phases were driedover sodium sulfate, filtered, and concentrated. The residue waspurified using a 12 gram Isco brand silica column and eluted with10-100% EtOAc/Heptane (30 mL/min), yielding the desired product as abright yellow amorphous solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.92(s, 1 H), 7.32 (s, 2 H), 5.88 (t, J=2 Hz, 1 H), 5.22 (s, 4 H), 3.50 (s,6 H), 2.66 -2.77 (m, 2 H), 2.57 (ddd, J=10, 5, 2 Hz, 2 H), 2.04 (t, J=7Hz, 2 H); LCMS Method A: t_(R)=0.94 min, 98%; MS (ESI): m/z 293.5 (M+H)⁺

Step 5

4-(Cyclopent-1-en-1-yl)-3,5-bis(methoxymethoxy)benzaldehyde (252 mg,0.862 mmol) was dissolved in a mixture of methanol (3451 μl) andtrimethyl orthoformate (2382 μl, 21.55 mmol) containing a catalyticamount of ammonium chloride (4.61 mg, 0.086 mmol). The mixture wasstirred at 65° C. for 2.5 h or until the benzaldehyde had been consumedas measured by NMR. The reaction mixture was cooled to rt and treateddropwise with triethylamine (481 μl, 3.45 mmol). After stirring at rtfor 5 min, water (1.5 mL) was added and the mixture was diluted withdiethyl ether (1.5 mL). The organic phase was separated and the aqueousphase was extracted with diethyl ether (3×10 mL). The organic phase waswashed with water (10 mL), dried over sodium sulfate, filtered, andconcentrated. The residue was dissolved in ethanol (3451 μl) and stirredunder hydrogen atmosphere (40 psi) in the presence of 10% palladium oncarbon (22.93 mg, 0.216 mmol) for 17.5h. LCMS revealed, ˜28% conversionto the desired product and ˜59% residual stating material. Additionalpalladium on carbon (22.93 mg, 0.216 mmol) was added and the reactionwas re-subjected to hydrogen atmosphere (40 psi) for an additional 6.5 h(24 h total). The reaction mixture was filtered and evaporated. Thecrude residue was dissolved in a 1:1 mixture of tetrahydrofuran (THF,2.374 mL) and 2N H₂SO₄ (2.374 mL) and stirred at rt for 2 h. The mixturewas diluted with EtOAc (1.5 mL) and water (1.5 mL), and the organicphase was separated. The aqueous phase was extracted with EtOAc (3×10mL) and the organic phase was washed with water (10 mL), saturatedaqueous sodium bicarbonate (10 mL), dried over sodium sulfate, filtered,and concentrated. The residue was purified using a 12 gram Isco brandsilica column and was eluted with 0-100% EtOAc/Heptane (30 mL/min),yielding the desired product as a colorless amorphous solid. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 9.89 (s, 1 H), 7.30 (s, 2 H), 5.26 (s, 4 H),3.77 (m, 1 H), 3.52 (s, 6 H), 1.79-2.04 (m, 6 H), 1.63-1.76 (m, 2 H);LCMS Method A: t_(R)=1.01 min, 92%; MS (ESI): m/z 295.5 (M+H)⁺

Step 6

A solution of 4-cyclopentyl-3,5-bis(methoxymethoxy)benzaldehyde (100 mg,0.340 mmol) in anhydrous dichloromethane (833 μL) was slowly added tomCPBA (64.5 mg, 0.374 mmol) in anhydrous dichloromethane (DCM, 3.331mL). The reaction mixture was warmed to rt, then refluxed for 12 h.After cooling to rt, the solution was extracted with DCM (3×10 mL). Thecombined organic layer was washed with saturated aqueous sodiumbicarbonate solution, and 10% aqueous sodium thiosulfate (10 mL), driedover sodium sulfate, filtered, and concentrated.

The residue was re-dissolved in methanol (0.67 mL) and stirred with 10%aqueous sodium hydroxide (0.679 mL, 16.99 mmol) for 3h at rt. The pH wasadjusted to 2 with 1N HCl and the solution was extracted withdichloromethane (3×10 mL). The combined organic layer was dried oversodium sulfate, filtered, and concentrated. The residue was purifiedusing a 4 gram Isco brand silica column and eluted with 0-100%EtOAc/Heptane (18 mL/min), yielding the desired compound as a yellowamorphous solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.35 (s, 2 H),5.15 (s, 4 H), 4.63 (s, 1 H), 3.59 (m, 1 H), 3.50 (s, 6 H), 1.72-1.98(m, 6 H), 1.61-1.72 (m, 2 H); LCMS Method A: t_(R)=0.89 min, 95%; MS(ESI): m/z 283.5 (M+H)⁺

Step 7

To a solution of 4-cyclopentyl-3,5-bis(methoxymethoxy)phenol (25.1 mg,0.089 mmol) in N,N-Dimethylformamide (DMF, 323 μl) was addedtriethylamine (24.78 μl, 0.178 mmol) and1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(47.6 mg, 0.133 mmol). The mixture was stirred at rt for 1 h. After 1 h,the progress of the reaction was analyzed by LCMS, revealing fullconsumption of starting material and conversion to product. Next, thereaction mixture was concentrated and the crude product was diluted withEt₂O (2.5 mL), washed with water (3×5 mL) and saturated aqueous sodiumchloride (5 mL), dried over sodium sulfate, filtered, and concentrated.The residue was purified using a 4 gram ISCO silica gel column (elutedwith 5-100% EtOAc/Heptane), yielding the desired product as a colorlessoil. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.75 (s, 2 H), 5.18 (s, 4 H),3.66 (m, 1 H), 3.50 (s, 6 H), 1.76-1.98 (m, 6 H), 1.63-1.75 (m, 2 H);LCMS Method A: t_(R)=1.18 min, 100%; MS (ESI): m/z 413.4 (M-H)⁻

Example 1A 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol Method A

Step 1

To a solution of isoquinolin-3-ol (300 mg, 2.067 mmol) and1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(923 mg, 2.58 mmol) in DCM (20 mL) was added TEA (0.864 mL, 6.20 mmol).The mixture was stirred at room temperature for 2 hrs, diluted withwater (25 mL) and extracted with DCM (30 mL×2). The DCM solution wascombined, washed with brine, dried, and concentrated. The crude materialwas purified by preparative TLC (eluted with petroleum ether/ethylacetate =50/1) to afford isoquinolin-3-yl trifluoromethanesulfonate (350mg, 1.136 mmol, 55.0% yield) as a colorless liquid. LCMS Method A:t_(R)=1.77 min, 100%; MS: m/z 277.8 (M+H)⁺

Step 2

In a nitrogen atmosphere, into a mixture of isoquinolin-3-yltrifluoromethanesulfonate (100 mg, 0.361 mmol) and2-(4-isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(133 mg, 0.433 mmol) in toluene (2 mL) and water (0.500 mL) was addedNa₂CO₃ (76 mg, 0.721 mmol). The reaction mixture was stirred at 80° C.for 5 h, cooled and purified by a reverse phase chromatography(CombiFlash 50 g reverse phase C18 column; gradient 20-50% MeOH in waterwith 0.01% TFA over 30 min). The fractions were combined andconcentrated. The residue was re-crystallized in water, and dried bylyophilization to afford 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline(90 mg, 0.190 mmol, 52.8% yield) as a white solid. LCMS Method A:t_(R)=1.81 min, 61%; MS: m/z 307.9 (M+H)⁺

Step 3a Method A

To a solution of 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline (90 mg,0.293 mmol) in dichloromethane (DCM, 2 mL) was added BBr₃ (0.138 mL,1.464 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hand purified by reverse phase chromatography (CombiFlash 50 g reversephase C18 column; loaded using MeOH; eluted with 20-50% MeOH/Water with10 mM TFA over 30 mins). The appropriate fractions containing productwere combined, re-crystallized in water, and dried by lyophilization toafford the title compound,2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (80 mg, 0.272 mmol, 93%yield), as a yellow solid. ¹H NMR (400 MHz, MeOD) δ 9.65 (s, 1H), 8.48(s, 1H), 8.44 (d, 1H), 8.26 (d, 1H), 8.16 (t, 1H), 7.96 (t, 1H), 6.83(s, 2H), 3.63 (sep., 1H), 1.37 (d, 6H); LCMS Method A: t_(R)=1.79 min,100%; MS: m/z 280.2 (M+H)⁺

Step 3b Method B

Step 3b-1

To a solution of 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline (3.8 g,12.36 mmol) in dichloromethane (DCM, 2 mL) was add BBr₃ (5.84 mL, 61.8mmol). The reaction mixture was stirred at 0° C. for 1 h. The solutionwas concentrated in vacuo, diluted with saturated NaHCO₃ and extractedwith ethyl acetate. The organic was washed with brine, dried over NaSO₄and concentrated to give the desired compound that was used withoutfurther purification. LCMS Method B: t_(R)=1.88 min, 53%; MS (ESI): m/z359.5 (M+2)⁺

Step 3b-2

To a solution of4-bromo-2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (3.4 g, 9.49mmol) in methanol (30 mL) was added 10% Pd/C (400 mg). The mixture wasstirred at room temperature under H₂ atmosphere for 1 h. The reactionmixture was filtered, and concentrated in vacuo to give 2.7 g of thecrude product that was purified by reverse phase chromatography (C18column; mobile phase, A: 10 mM TFA aqueous solution; B: MeOH; gradient:10 min, 9-71% B) to afford2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol) as a gray solid. ¹HNMR (500 MHz, MeOD) δ 9.26 (s, 1H), 8.10 (d, 1H), 8.06 (s, 1H), 7.96 (d,1H), 7.79 (t, 1H), 7.66 (t, 1H), 6.97 (s, 2H), 3.59 (sep., 1H), 1.37 (d,6H); LCMS Method B: t_(R)=2.08 min, 98.4%; MS (ESI): m/z 280.0 (M+H)⁺

Example 1B 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol Method B

Stage 0

Isoquinolin-3-yl trifluoromethanesulfonate

DCM (6 vol) was charged into the reactor followed by addition ofisoquinolin-3-ol (1.0 eq), Et₃N (1.45 eq) andN-benzyl-bis-trifluoromethanesulphonimide (1.1 eq.). The reactionmixture was stirred at 20-35° C. for 2-3 h. After completion, water (10vol) was charged into the reaction mixture and stirred for 15 min. Theorganic and aqueous layers were separated. The organic layer was washedwith water (10 vol). The organic and aqueous layers were separated, andthe organic layer was dried over Na₂SO₄. The organic layer was thenfiltered to remove the Na₂SO₄ and concentrated under reduced pressure at35-40° C. to afford the crude as a black liquid. The crude was chargedinto the reactor. Ethyl acetate (6.0 vol), followed by charcoal (0.1w/w) were added. The contents were heated to 55-60° C. for 30 min, andthen cooled to 20-35° C. The contents were filtered through Celite andwashed with ethyl acetate (5 vol). The combined organic layer wasconcentrated under reduced pressure at 40-45° C. to afford a dark brownliquid. The dark brown liquid was charged into the reactor followed bythe addition of heptane (20 vol), and the contents were heated to 60-65°C. for 1 h. The contents were filtered at 60-65° C. through a layer ofcelite (lot-2), and washed with heptane (5 vol). The combined heptanelayers were concentrated under reduced pressure at 40-45° C. to affordthe desired product Compound 6 as a light yellow liquid which becomessolid at 2-8° C.

Stage 1

1-(2,6-dimethoxyphenyl)ethanone

2,6-Dihydroxy acetophenone (1.0 eq) and potassium carbonate (5.0 eq)were taken up in acetone (14 vol) at 20-35° C. Dimethyl sulphate (2.5eq) was added to the contents while at the same temperature. Thecontents were heated to 60-65° C. (reflux) for 2-3 h, and monitored byIPC-HPLC. The reaction mixture was cooled to 20-35° C., the saltsfiltered off and rinsed with acetone (5 vol). The combined organic layerwas concentrated under reduced pressure to yield the crude liquidproduct. Water (30 vol) was added to the crude material and the mixturewas stirred for 1 h at 20-35° C. The resulting solid was filtered offand washed with water (5 vol), and the wet cake was transferred into around bottom flask. Saturated NaHCO₃ (10 vol) was added and the contentsstirred for 1 h. The contents were filtered to remove the solids, andthe solids were rinsed with water (lot-3, 5 vol) to afford the productCompound 2 as an off-white solid. The solid was then dried at 40-45° C.until the KF reading showed <1%.

Stage 2

1,3-dimethoxy-2-(prop-1-en-2-yl)benzene

MeMgBr (1.4 M, 1.5 eq) was added to a round bottom flask under nitrogenat 20-35° C. The contents were cooled to 0-10° C. A solution of Compound2 (1.0 eq) dissolved in THF (10 vol) was then added to the cooledGrignard solution while the temperature was maintained at 0-10° C. Thereaction mixture was warmed to room temperature and stirred for 2 h.After 2 h, the reaction mixture was cooled to 0-10° C. A solution of 4 NHCl was added, and the contents allowed to warm to room temperature andstirred for another 2 h. Following this, ethyl acetate (7 vol) was addedand the contents were stirred for 30 min. The layers were allowed toseparate, and the aqueous layer was extracted with ethyl acetate (3.5vol). The organic fractions were combined and washed with water (10vol). The layers were allowed to separate, the aqueous layer wasdiscarded, and the organic layer was again washed with water (10 vol).The layers were allowed to separate, the aqueous layer was discarded,and the organic layer was washed with sat. NaHCO₃ (10 vol). The layerswere again allowed to separate, the sat. NaHCO₃ layer was discarded, andthe organic layer was washed a final time with water (10 vol). Theorganic layer was dried over Na₂SO_(4.) Following drying, the sodiumsulfate was filtered off and the solvent was removed under reducedpressure at 40-45° C. to afford 1,3-dimethoxy-2-(prop-1-en-2-yl)benzeneCompound 3 as a crude liquid which was used as is in the next stage.

Stage 3

2-isopropyl-1,3-dimethoxybenzene

Ethyl acetate (10 vol) was charged to the reactor followed by1,3-dimethoxy-2-(prop-1-en-2-yl)benzene (1.0 eq) and the contents werestirred at 25-35° C. until it became a clear solution. 10% Pd/C (0.1w/w) was added to the reactor and the contents were purged under vacuumbefore being placed under H₂ . The contents were then stirred at 25-35°C. for 4 h. Following this, the reaction mixture was filtered throughCelite and washed with ethyl acetate (5 vol). The combined organicfractions were reduced in volume under vacuum at 40-45 ° C. to afford2-isopropyl-1,3-dimethoxybenzene Compound 4 as a crude liquid which wasused as is in the next stage.

Stage 4

2-(4-isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

THF (7 vol) was charged into the reactor and degassed with N₂ for 30min. The iridium catalyst (0.0081 eq), catalyst ligand (0.017 eq),bis-pinacolatodiboron (1.0 eq) and 2-isopropyl-1,3-dimethoxybenzene (1.0eq) were added in order to the reactor. The reaction mixture wasrefluxed at 80° C. for 60 h. The contents were filtered through Celite(0.5 w/w) and washed with ethyl acetate (2.5 vol). The combined organiclayer was reduced in volume under vacuum at 40-45° C. to afford thecrude product as a thick black syrup, which was crystallized fromhexanes (5 vol) to give2-(4-isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneCompound 5 as a light brown solid.

Stage 5

3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline

1,4-Dioxane (8 vol) and water (2 vol) was charged into the reactor anddegassed for 20 min. Compound 6 (1.3 eq) was charged into the reactorand degassed for 10 min.2-(4-Isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Compound 5, Stage 4 product, 1.0 eq) was added and the contents weredegassed for another 10 min, followed by the addition of the palladiumcatalyst (0.1 eq). The contents were degassed for an additional 15 min,and then heated to 85-89° C. for 3 h. The reaction mixture was cooled to20-35° C., and water (20 vol) was charged into the reactor, and thecontents stirred for 1-2 h. The contents were filtered through a Buchnerfunnel, and washed with water (5 vol) resulting in a crude black solid.The solid was taken up in ethyl acetate (10 vol) and charged into thereactor. Charcoal (0.5 w/w) was charged to the reactor, and the contentswere then heated to 60-70° C. for 1 h. The contents were cooled to20-35° C., and filtered through Celite, and the solids washed with ethylacetate (2.5 vol). The combined organic layer were concentrated underreduced pressure at 40-45 ° C. to give a viscous liquid. Heptane (1.0vol) was added to the liquid and distilled. Heptane (0.5 vol) was addedand distilled again to afford3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline Compound 7 as a brownsolid.

Stage 6

2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol

2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol Compound 7 (1.0 eq) wascharged into the reactor and 33% HBr in acetic acid (15 vol) was addedat 20-35° C. The contents were heated to 95-100° C. for 24 h. Thecontents were then transferred into a second reactor containing water(25 vol), and stirred at 20-35° C. for 2 h. The salt which had formedwas filtered through a Buchner funnel and rinsed with water (5 vol). Thewet salt cake was added into the reactor. Ethyl acetate (10 vol) wasadded to the reactor, followed by sat. NaHCO₃ soln. (10 vol). Thecontents were stirred at 20-35° C. for 30 min. Stirring was stopped andthe layers were allowed to separate. The aqueous layer was decanted off,and the organic layer was washed with water (10 vol). The phases wereallowed to separate, the aqueous layer was drawn off, and the organiclayer was dried over Na₂SO_(4.) The sodium sulfate was filtered off andrinsed with ethyl acetate (5 vol). The combined organic layer wasreduced in volume under vacuum at 40-45° C. to afford the crude freebase as a dark black solid. The crude free base was charged into thereactor, followed by ethyl acetate (6.7 vol), silica (1.0 w/w) andlastly charcoal (1.0 w/w) at 20-35° C. The contents were heated to60-70° C. for 1 h, and then cooled 20-35° C. The contents were filteredthrough Celite (0.5 w/w), and washed with ethyl acetate (3.35 vol). Thecombined organic layer was reduced in volume by distillation to afford agummy solid. Heptane (1.34 vol) was charged to the reactor, and thecontents again distilled down. Heptane (1.34 vol) was again charged tothe reactor, and the contents distilled down to afford a light brownsolid. 1,4-Dioxane (10 vol), silica (1.0 w/w) and charcoal (1.0 w/w;Noret CGP) were charged to the reactor at 20-35° C. The contents wereheated to 60-70° C. for 1 h., and then cooled to 20-35° C. The contentswere filtered through Celite (0.5 w/w) and washed with 1,4-dioxane(lot-2, 3×5 vol). The combined organic layers were reduced under vacuumat 40-45° C. to afford 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol,compound of Formula 8 as an off-white solid.

Stage 7

2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol

2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, compound of Formula 8was charged into the reactor, followed by isopropyl alcohol at 20-35° C.The heterogeneous mixture was heated to 65-70° C. until it becomes aclear solution, then heptane was added (16 vol) slowly over a period of20-30 min at 65-70° C. The reaction mixture was maintained at 65-70° C.for 1 h, then cooled to 0-5° C. and held for 1 h. The solid was filteredoff at 20-35° C. and washed with heptane (2 vol) which afforded2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, as an off-white solid.

Example 2 3-(3-Aminopropoxy)-2-isopropyl-5-(isoquinolin-3-yl)phenol,bis-trifluoroacetic acid salt

Into a solution of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (185mg, 0.662 mmol) in N,N-Dimethylformamide (DMF, 4 mL) was added 60%sodium hydride oil dispersion (35 mg, 0.875 mmol) at room temperaturewith magenetic stirring. After hydrogen evolution ceased, tent-butyl(3-bromopropyl)carbamate (178 mg, 0.748 mmol) was added. The resultantmixture was heated at 50° C. overnight. LCMS revealed a mixture of thestarting material, mono-alkylated and di-alkylated product (nearly1:1:1). The mixture was cooled, quenched with water (25 mL) and filteredto collect a greenish gray solid. The crude material was dissolved inMeOH and purified by Gilson prep-HPLC [Luna acidic on an Agilent Eclipseplus C18 column (5 μm, 30×50 mm), gradient 30-60% acetonitrile/waterwith 0.1% TFA, 47 mL/min flow rate, 14 min run time, fractions collectedfrom 3.5 min to 4.2 min]. The residue with m/z=437.5 (M+1)⁺ on LCMS fromevaporation of the corresponding fractions was dissolved in DCM (5 mL)and treated with TFA (1 mL) at rt overnight. The reaction mixture wasconcentrated to dryness under reduced pressure to afford the desiredcompound as a yellow amorphous solid. ¹H NMR (400 MHz, METHANOL-d₄) δppm 9.76 (s, 1 H), 8.61 (s, 1 H), 8.48 (d, J=8 Hz, 1 H), 8.29 (d, J=8Hz, 1 H), 8.19 (t, J=7 Hz, 1 H), 7.97 (t, J=7 Hz, 1 H), 6.98-7.11 (m, 2H), 4.26 (t, J=6 Hz, 2 H), 3.69 (dt, J=14, 7 Hz, 1 H), 3.24 (t, J=8 Hz,2 H), 2.18-2.35 (m, 2 H), 1.37 (d, J=7 Hz, 6 H); LC/MS: m/z=337.3(M+1)⁺,t_(R)=0.52 min, 100%.

Example 3N-(2-Aminoethyl)-3-(3,5-dihydroxy-4-isopropylphenyl)isoquinoline-6-carboxamide

Step 1

A mixture of 6-bromoisoquinolin-3(2H)-one (5 g, 22.32 mmol), PdCl₂(dppf)(1.633 g, 2.232 mmol) and Et₃N (6.22 mL, 44.6 mmol) in methanol (10 mL)was placed in a pressure vessel. The vessel was purged with nitrogenthree times, charged with 300 kPa of carbon monoxide and heated at 100°C. for 20 h. The reaction mixture was cooled and concentrated to givecrude methyl 3-oxo-2,3-dihydroisoquinoline-6-carboxylate as a yellowsolid that was used at the next step directly. LCMS: m/z=204.0,t_(R)=1.19 min.

Step 2

A solution of methyl 3-oxo-2,3-dihydroisoquinoline-6-carboxylate (1 g,2.461 mmol) and pyridine (0.389 g, 4.92 mmol) in POCl₃ (5 mL) in asealed tube was stirred at 160° C. for 16 h. The mixture was cooled andpoured into ice-water (20 mL). The solid was filtered and dissolved inethyl acetate (30 mL). The filtrate was extracted with ethyl acetate (10mL×3). The combined organic phase was washed with water/brine, driedover Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (30 g) with petroleumether/dichloromethane/methanol (1/1/0.05) to yield methyl3-chloroisoquinoline-6-carboxylate (130 mg, 0.557 mmol, 22.64% yield) asa yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm=9.34 (s, 1H), 8.67 (s,1H), 8.30 (d, J=12.0, 2H), 8.14 (d, J=8.8, 1H), 3.96 (s, 3H); LCMS:m/z=221.9, t_(R)=1.57 min.

Step 3

A mixture of methyl 3-chloroisoquinoline-6-carboxylate (100 mg, 0.451mmol),2-(4-isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(145 mg, 0.474 mmol), Na₂CO₃ (143 mg, 1.354 mmol), and PdCl₂(dppf) (33.0mg, 0.045 mmol) in 1,4-dioxane (10 mL) and water (1.0 mL) was stirredunder nitrogen at 100° C. for 16 h. The solvents were removed underreduced pressure. LCMS: m/z=365.9(M+1)⁺, t_(R)=1.94 min, 80%. The crudeproduct (150 mg) was used at the next step directly.

Step 4

A mixture of methyl3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline-6-carboxylate (150 mg,0.410 mmol) and NaOH (49.3 mg, 1.231 mmol) in THF (4 mL) and water (4.00mL) was stirred under nitrogen at rt for 16 hr then diluted with water(10 mL). The mixture was washed with ethyl acetate (15 mL×3), adjustedto pH 1-2 with 1N HCl and extracted with ethyl acetate (15 mL×3). Thecombined organic phase was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to afford3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline carboxylic acid (100 mg)as a pale yellow solid. The crude product was used at the next step.LCMS: m/z=351.9(M+1)⁺, t_(R)=1.72 min, 82%.

Step 5

A solution of3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline-6-carboxylic acid (100mg, 0.285 mmol), HATU (162 mg, 0.427 mmol) and DIEA (0.149 mL, 0.854mmol) in N,N-Dimethylformamide (DMF, 5 mL) was stirred under nitrogen atrt for 1 hr. Tert-Butyl (2-aminoethyl)carbamate (54.7 mg, 0.341 mmol)was added. The reaction mixture was stirred at 25° C. for 12 h, quenchedwith ice water (10 mL) and extracted with ethyl acetate (15 mL×5). Thecombined organic phase was washed with water/brine, dried over Na₂SO₄and concentrated in vacuo. The residue was purified by preparative HPLC(Gemini C18 150×21.2 mm, 5 um, one injections mobile phase: ACN-H₂O,gradient: 10-60%) to afford tent-butyl(2-(3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline-6-carboxamido)ethyl)carbamate(70 mg, 0.135 mmol, 47.3% yield) as a pale yellow solid. ¹H NMR (400MHz, DMSO-d6) δ ppm=9.47 (s, 1H), 8.79 (t, 1H), 8.56 (s, 1H), 8.53 (s,1H), 8.22 (d, J=8.8, 1H), 8.04 (d, J=8.4, 1H), 7.49 (s, 2H), 6.98 (t,1H), 3.91 (s, 6H), 3.64-3.57 (m, 1H), 3.37 (dd, 2H), 3.17 (d, J=5.6,2H), 1.39 (s, 9H), 1.28 (d, J=7.2, 6H); LCMS: m/z=493.8(M+1)⁺,t_(R)=1.77 min, 95%.

Step 6

To a solution of tent-butyl(2-(3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline-6-carboxamido)ethyl)carbamate(60 mg, 0.122 mmol) in DCM (10 mL) stirred in nitrogen atmosphere at−30° C. was added BBr₃ (0.575 mL, 6.08 mmol). The reaction mixture wasstirred at 25° C. for 3 h, poured onto ice, neutralized with NaOH (1N)until pH=7, and extracted with EtOAc (10 mL×5). The combined organicextract was washed with brine, dried over Na₂SO₄, and concentrated. Thelight yellow residue was purified by preparative HPLC (Gemini C18150×21.2 mm 5 um, mobile phase: ACN-H₂O with 0.1% TFA, gradient: 10-30%)to affordN-(2-aminoethyl)-3-(3,5-dihydroxy-4-isopropylphenyl)isoquinoline-6-carboxamide(30 mg, 0.080 mmol, 66.2% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO) δ ppm 9.42 (s, 1H), 9.26 (s, 1H), 8.56 (s, 1H), 8.41 (s, 2H), 8.20(d, J=8.4, 1H), 8.11 (s, 1H), 8.05 (d, J=8.4, 1H), 7.15 (s, 2H), 4.20(brs, 2H), 3.54-3.47 (m, 3H), 3.00 (s, 2H), 1.29 (d, J=6.8, 6H); LCMS:m/z=365.9(M+1)⁺, t_(R)=1.200 min, 98.7%.

Example 4: Crystal Form Screen of2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol

A crystal form screen was performed on2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol. The screen consistedof ˜160 experiments using 60 solvent systems, and identified 16 variouscrystal forms including: a non-solvated form (Group A); two hydrateforms (Groups M and H); 8 stable organic solvates; and 5 putativeorganic solvates that were unstable and converted to other forms atambient conditions.

Of the ˜160 total experiments, 83 of these experiments yielded solidsfor analysis. Of those, 39 experiments yielded the non-solvate group Aform (also known as form 2); 22 yielded amorphous material; only 5yielded a hydrate (3 group H, 2 group M); and the remaining 17 resultedin one of the remaining 13 observed forms. These results are shownvisually in Tables 1 and 2 below.

TABLES 1 Products of Slurry-Ripening, Cooling, and EvaporationCrystallization Form Slurry- # Solvent (v/v) Ripening CoolingEvaporation 1 Water A3 NS amorphous 2 MeOH/Toluene (1:9) NS NS A 32-methoxyethanol/i-propyl ether NS NS A¹ (1:9) 4 1-propanol/diethylether (1:8) NS NS A 5 Nitromethane/i-propyl ether (5:90) A NS amorphous¹6 MeCN B B B¹ 7 DMSO/diethyl ether(1:9) NS NS amorphous¹ 8Acetone/heptane (1:9) C C NS 9 2-butanone/cyclohexane (1:9) A³ F F 10DCM A³ NS A¹ 11 Methylacetate/cyclohexane (1:9) A³ NS amorphous¹ 12MIBK/toluene (3:7) A³ NS amorphous¹ 13 Chloroform A NS A¹ 14EtOAc/heptane (1:9) A³ NS A 15 Chlorobenzene A³ NS amorphous¹ 16Tetrahydrofuran/heptane (1:9) A³ NS NS 17 1,4-dioxane/i-propyl ether(1:9) A³ NS amorphous¹ 18 i-propyl ether A³ NS amorphous¹ 19 Toluene A³NS NS 20 Cyclohexane A³ NS NS ² 21 heptane A³ NS NS 22 1-butanol/toluene(3:7) NS NS L 23 IPA/i-propyl ether (2:8) NS NS amorphous¹ 24Trifluoroethanol/toluene (1:9) A³ NS A 25 Dimethylcarbonate A³ A J 26MTBE A³ NS amorphous¹ 27 i-propyl acetate/toluene (2:7) A³ NS A¹ 28EtOH/Toluene (2:8) NS NS amorphous¹ 29 1-methoxy-IPA/heptane (10:95) NSNS amorphous¹ 30 Cyclohexanone/diethyl ether (5:95) NS NS amorphous¹ 31N,N-dimethylformamide/water D NS amorphous (2:8) 32 2-methoxy methylether/Isopropyl NS NS amorphous¹ ether (5:5) 33 MeOH/water (95:5) NS NSamorphous¹ 34 MeCN/water (95:5) B B B¹ 35 acetone/water (95:5) NS NSamorphous¹ 36 THF/water (95:5) NS NS D, N 37 IPA/water (95:5) NS NSamorphous¹ 38 MeOH/water (2:9) A³ NS 39 MeCN/water (1:9) A³ NS amorphous40 acetone/water (1:9) A³ NS amorphous 41 THF/water (2:8) NS D, N H 421,4-dioxane/water (1:9) E NS NS 43 IPA/water (5:5) A NS H¹ 44acetone/water (5:5) NS NS H 45 dioxane/water (5:5) NS NS E 46EtOAc/cyclohexane (1:2) A³ NS A 47 EtOAc/toluene (1:2) A NS A¹ 48MIBK/heptane (1:2) A³ NS amorphous¹ 49 MeOH NT NT A 50 EtOAC NT NT I¹discoloration; ² not enough solid for analysis; ³purified off-whitesolids A = non solvate; B = MeCN/water solvate; C = acetone solvate; D =DMF solvate; E = 1,4-dioxane/water solvate; F = butanone solvate(putative); G = THF/water solvate; H = hydrate; I = EtOACsolvate(putative); J = DMC solvate (putative); K = DMSOsolvate(putative); L = 1-butanol solvate; M = hydrate (when scaled up);N = THF solvate; O = THF solvate (putative); P = MTBE solvate; NS = nosolid; NE = no experiment

TABLE 2 Products of Solvent/Antisolvent Crystallization # SolventAntisolvent Group 1 MeOH diethyl ether NS 2 MeOH i-propyl ether NS 3MeOH MTBE NS 4 IPA diethyl ether amorphous 5 IPA i-propyl ether NS 6 IPAMTBE NS 7 EtOAC diethyl ether NS 8 EtOAC MTBE NS 9 EtOAC pentane A 10DMSO water K 11 DMSO MTBE NS 12 DMSO toluene NS A = non solvate; K =DMSO solvate(putative); NS = no solid

Some embodiments describe a process for making a compound of Formula (I)which comprises treating a compound of Formula (A)

or a salt thereof;wherein,

R³ is selected from the group consisting of optionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted aryl, optionally substituted aryl C₁₋₆alkyl, optionally substituted C₃₋₆ cycloalkyl, optionally substitutedC₄₋₆ cycloalkenyl, halo, cyano, —C(O)OR⁸, —NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰ ,—C(O)R¹¹, —OR¹², —S(O)_(n)R¹³, and an optionally substitutedheterocyclic ring;

R⁸ is independently selected from the group consisting of H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,optionally substituted aryl, and optionally substituted aryl C₁₋₆ alkyl;

each of R⁹ and R¹⁰ is independently selected from the group consistingof H, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substituted aryl, optionally substituted arylC₁₋₆ alkyl, or alternatively, R⁹ and R¹⁰ together with the nitrogen atomto which they are attached form a 5-7 membered cyclic saturated orunsaturated ring;

R¹¹ is independently selected from the group consisting of H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted aryl, optionallysubstituted aryl C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,—NR⁹R¹⁰, and —OR¹²;

each of R¹² and R¹³ is independently selected from the group consistingof H, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted aryl C₁₋₆ alkyl, and optionally substituted C₃₋₆ cycloalkyl;

R⁶ is selected from the group consisting of H, halo, hydroxyl, alkoxy,optionally substituted C₁₋₆ alkyl, halogenated alkyl; optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, andoptionally substituted aryl C₁₋₆ alkyl;

n is an integer having a value of 0, 1 or 2;

s is an integer having a value of 0, 1 or 2;

t is an integer having a value of 0 to 6;

R^(5c) is selected from the group consisting of H, halo, optionallysubstituted C₁₋₆ alkyl, —C(O)OR¹⁴, —C(O)NR¹⁵R¹⁶, aryl and —C₁₋₆alkylaryl;

R¹⁴ is independently selected from the group consisting of H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,optionally substituted aryl, and optionally substituted aryl C₁₋₆ alkyl;

each of R¹⁵ and R¹⁶ is independently selected from the group consistingof H, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substituted aryl, optionally substituted arylC₁₋₆ alkyl, and optionally substituted C₃₋₆ cycloalkyl; alternativelyR¹⁵ and R¹⁶ together with the nitrogen to which they are attached, forma 5-7 membered cyclic saturated or unsaturated ring;

R^(4c) is selected from the group consisting of H, halo, cyano,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted aryl,optionally substituted aryl C₁₋₆ alkyl, optionally substituted C₃₋₆cycloalkyl, —(CR¹⁸R¹⁹)_(t)COOR⁸, —(CR¹⁸R¹⁹)_(t)OC(O)R⁸,—(CR¹⁸R¹⁹)_(t)NR⁹R¹⁰, —(CR¹⁸R¹⁹)_(t)C(O)NR⁹R¹⁰, —(CR¹⁸R¹⁹)_(t)NR⁹C(O)R⁸,—(CR¹⁸R¹⁹)_(t)S(O)₂NR⁹R¹⁰, —(CR¹⁸R¹⁹)_(t)COR¹¹, —(CR¹⁸R¹⁹)_(t)CH(O),—(CR¹⁸R¹⁹)_(t)OR¹², —(CR¹⁸R¹⁹)_(t)S(O)_(s)R¹³, optionally substitutedheterocyclic, and optionally substituted heterocyclic C₁₋₆ alkyl; and

each of R¹⁸ and R¹⁹ is independently selected from the group consistingof H, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substituted aryl, and optionally substituted arylC₁₋₆ alkyl;

with boron tribromide dissolved in a suitable organic solvent, such asmethylene chloride, with stirring for a sufficient time and temperature,and then adding a suitable alcohol, such as CH₃OH to yield a compound ofFormula (I), wherein R⁶ is hydrogen.

Another aspect of the invention is a process for making a compound ofFormula (I) which comprises treating a compound of Formula (B)

or a salt thereof; wherein

R³ is selected from the group consisting of optionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted aryl, optionally substituted aryl C₁₋₆alkyl, optionally substituted C₃₋₆ cycloalkyl, optionally substitutedC₄₋₆ cycloalkenyl, halo, cyano, —C(O)OR⁸, —NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰ ,—C(O)R¹¹, —OR¹², —S(O)_(n) R¹³, and an optionally substitutedheterocyclic ring;

R⁸ is independently selected from the group consisting of H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,optionally substituted aryl, and optionally substituted aryl C₁₋₆ alkyl;

each of R⁹ and R¹⁰ is independently selected from the group consistingof H, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substituted aryl, optionally substituted arylC₁₋₆ alkyl, or alternatively, R⁹ and R¹⁰ together with the nitrogen atomto which they are attached form a 5-7 membered cyclic saturated orunsaturated ring;

R¹¹ is independently selected from the group consisting of H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted aryl, optionallysubstituted aryl C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,—NR⁹R¹⁰, and —OR¹²;

each of R¹² and R¹³ is independently selected from the group consistingof H, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted aryl C₁₋₆ alkyl, and optionally substituted C₃₋₆ cycloalkyl;

n is an integer having a value of 0, 1 or 2;

s is an integer having a value of 0, 1 or 2;

t is an integer having a value of 0 to 6;

R^(5b) is selected from the group consisting of H, halo, optionallysubstituted C₁₋₆ alkyl, —C(O)OR¹⁴, —C(O)NR¹⁵R¹⁶, aryl and —C₁₋₆alkylaryl;

R¹⁴ is independently selected from the group consisting of H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,optionally substituted aryl, and optionally substituted aryl C₁₋₆ alkyl;

each of R¹⁵ and R¹⁶ is independently selected from the group consistingof H, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substituted aryl, optionally substituted arylC₁₋₆ alkyl, and optionally substituted C₃₋₆ cycloalkyl; alternativelyR¹⁵ and R¹⁶ together with the nitrogen to which they are attached, forma 5-7 membered cyclic saturated or unsaturated ring;

R^(4b) is selected from H, halo, cyano, optionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted aryl, optionally substituted aryl C₁₋₆alkyl, optionally substituted C₃₋₆ cycloalkyl, —(CR¹⁸R¹⁹)_(t)COOR⁸,—(CR¹⁸R¹⁹)_(t)OC(O)R⁸, —(CR¹⁸R¹⁹)_(t) NR⁹R¹⁰, —(CR¹⁸R¹⁹)_(t)C(O)NR⁹R¹⁰,—(CR¹⁸R¹⁹)NR⁹C(O)R⁸, —(CR¹⁸R¹⁹)_(t)S(O)₂NR⁹R¹⁰, —(CR¹⁸R¹⁹)_(t)COR¹¹,—(CR¹⁸R¹⁹)_(t)CH(O), —(CR¹⁸R¹⁹)_(t)OR¹², —(CR¹⁸R¹⁹)_(t)S(O)_(s)R¹³,optionally substituted heterocyclic, and optionally substitutedheterocyclic C₁₋₆ alkyl; and

each of R¹⁸ and R¹⁹ is independently selected from the group consistingof H, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substituted aryl, and optionally substituted arylC₁₋₆ alkyl;

under hydrogenation conditions, such as with 5-10% palladium on carbon,under hydrogen atmosphere at ambient temperature in a suitable organicsolvent, such as methanol, ethanol, isopropanol, ethyl acetate,tetrahydrofuran to yield a compound of Formula (I), wherein R⁶ ishydrogen.

Another aspect of the invention is the novel intermediate compounds ofFormula (II)

wherein

each of R¹ and R² is independently selected from the group consisting ofOH, OR⁷, and H, provided that at least one of R¹ and R² is —OH or —OR⁷;

R⁷ is independently selected from the group consisting of optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,optionally substituted aryl, aryl C₁₋₆ alkyl and acyl;

R³ is selected from the group consisting of optionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted aryl, optionally substituted aryl C₁₋₆alkyl, optionally substituted C₃₋₆ cycloalkyl, optionally substitutedC₄₋₆ cycloalkenyl, halo, cyano, —C(O)OR⁸, —NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰ ,—C(O)R¹¹, —OR¹², —S(O)_(n)R¹³, and an optionally substitutedheterocyclic ring;

R⁸ is selected from the group consisting of H, optionally substitutedC₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl, optionallysubstituted aryl, and optionally substituted aryl C₁₋₆ alkyl;

each of R⁹ and R¹⁰ is independently selected from the group consistingof H, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substituted aryl, and optionally substituted arylC₁₋₆ alkyl, or alternatively, R⁹ and R¹⁰ together with the nitrogen atomto which they are attached form a 5-7 membered cyclic saturated orunsaturated ring;

R¹¹ is independently selected from the group consisting of H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted aryl, optionallysubstituted aryl C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,—NR⁹R¹⁰ , and —OR¹²;

each of R¹² and R¹³ is independently selected from the group consistingof H, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted aryl C₁₋₆ alkyl, and optionally substituted C₃₋₆ cycloalkyl;

R⁶ is selected from the group consisting of H, halo, hydroxyl, alkoxy,optionally substituted C₁₋₆ alkyl, halogenated alkyl; optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, andoptionally substituted aryl C₁₋₆ alkyl;

n is an integer having a value of 0, 1 or 2;

In some embodiment, when R³ of Formula II is an optionally substitutedmoiety, the moiety may be substituted independently one or more times.In some embodiments when R³ of Formula II is an optionally substitutedmoiety, the moiety may be substituted independently one to three times.In some embodiments, the moieties may be optionally substitutedindependently one to three times with halo, hydroxy, C₁₋₃ alkoxy, C₁₋₃alkyl, aryl or arylalkyl.

In some embodiment R³ of Formula II is an optionally substituted C₃₋₆alkyl or optionally substituted C₃₋₆ cycloalkyl. In some embodiments,the C₃₋₆ alkyl is selected from the group consisting of isopropyl,n-propyl, n-butyl, t-butyl, sec-butyl, n-pentyl, isopentyl, 2-methylbutyl, n-hexyl, and the like. In one embodiment, the alkyl is isopropylgroup or t-butyl. In another embodiment, the alkyl is isopropyl. In oneembodiment, the cycloalkyl is a cyclopropyl, cyclopentyl or cyclohexyl.In another embodiment, the cycloalkyl is a cyclopentyl.

In some embodiments, R⁶ of Formula II is H.

Biological Data

As stated above, the compounds according to any embodiment describedherein are regulators of AhR and are useful in the treatment orprevention of human diseases that exhibit an inflammatory component.

The biological activity of the compounds according to any embodimentdescribed herein can be determined using any suitable assay fordetermining the activity of a candidate compound as an agonist orantagonist of AhR, as well as using tissue and in vivo models.

The biological activity of the compounds according to any embodimentdescribed herein are demonstrated by the following tests.

Example 5: CYP1A1-bla LS-180 AhR Agonist Assay

LS-180 cells stably transfected with a CYP1A1 promoter-linkedbeta-lactamase gene reporter construct (termed CYP1A1-bla LS-180 cells)were used to characterize the ability of compounds to activate AhR. Inbrief, AhR activity was measured using the LiveBLAzer assay kit whichutilizes a beta lactamase (bla) reporter gene downstream of CYP1A1promoter, which metabolizes its substrate to give a fluorescent readout.For the agonist assay, CYP1A1-bla LS-180 cells were treated withincreasing concentrations of compound over a 100,000-fold concentrationrange.

CYP1A1-bla LS-180 cells in exponential growth phase were washed twicewith DPBS then seeded into 96-well microplates (50,000 cells/well) andallowed to adhere. Prepared compounds (2× working concentrations incomplete media) were then added to the culture wells and cells wereincubated for ˜20 hrs. The LiveBLAzer FRET B/G β-lactamase substrate wasadded in the final hour of incubation and resulting blue/greenfluorescence was measured using a 96-well microplate reader.

AhR activity was measured as a function of beta-lactamase expressionusing a fluorescence resonance energy transfer-based readout. TCDD andFICZ were used as controls to validate the system. As expected,CYP1A1-bla LS-180 cells treated with TCDD displayed a conventionaldose-response relationship and TCDD exhibited a similar potency(pEcucC₅₀=10.34) to that reported by Invitrogen (pEC₅₀=9.70). CYP1A1-blaLS-180 cells treated with FICZ also displayed a conventionaldose-response relationship and, as predicted from the literature, FICZexhibited a much lower potency (pEC₅₀=6.82) than TCDD.

For these experiments, compounds of the invention, represented asExamples 1-3, demonstrated a pEC₅₀ of ≥6.0 (representing an EC₅₀≤1 μM)which is considered a positive response.

Example 6: CYP1A1-bla LS-180 AhR Antagonist Assay

A similar assay was used to evaluate the antagonist capacity ofcompounds. CYP1A1-bla LS-180 cells in exponential growth phase werewashed twice with DPBS then seeded into 96-well microplates (50,000cells/well) and allowed to adhere. Either FICZ or TCDD was added as anagonist and prepared compounds (2× working concentrations in completemedia) were added 2 hours later. Cells were incubated for ˜20 hrs, afterwhich compounds were tested for their ability to compete FICZ- orTCDD-induced AhR activation as a means to evaluate potential allostericor partial agonist activity. The LiveBLAzer FRET B/G β-lactamasesubstrate was added in the final hour of incubation and resultingblue/green fluorescence was measured using a 96-well microplate reader,as described above.

Compounds of the invention, represented as2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, was found to benegative in this assay.

Example 7 CD4+ T cell IL17 assay

AhR activation has been shown to modify transcriptional regulation ofthe immune system and specifically may affect the differentiation ofTh17 and Treg cells. Therefore, compounds are evaluated for theirability to reduce IL-17 production from CD4+ T cells stimulated underTh17-skewing conditions. Cryopreserved human CD4⁺ T cells (AllCells,LLC, Alameda, Calif. and Stemcell Technologies, Inc. Vancouver, Canada)were differentiated to the Th17 subtype by culturing for 5 days inCD3-coated tissue culture plates (2 μg/mL) in Iscove's modifiedDulbecco's medium (IMDM) containing 10% HI-FBS, 55 μM 2-mercaptoethanoland soluble anti-CD28 (3 μg/mL) in the presence of a Th17 skewingcocktail, [IL-1β (10 ng/mL), IL-6 (30 ng/mL), TGFβ (0.5 ng/mL), IL-21(10 ng/mL), IL-23 (10 ng/mL), anti-IFNγ (10 μg/mL) and anti-IL-4 (10μg/mL)] in the presence or absence of serially diluted compounds.Secretion of IL-17 from polarized CD4+ T-cells was measured in theculture media using an MSD (Meso Scale Discovery) detection systemfollowing 5 day exposure to Th17 polarization reagents with and withoutcompounds.

For these experiments, compounds of the invention all demonstrated apIC₅₀ of ≥6.0 (representing an IC₅₀≤1 μM) which is considered a positiveresponse for IL-17 inhibition.

Example 8: IMQ-Mouse Model of In Vivo Anti-Inflammatory Activity

Efficacy of AhR agonist compounds has been observed in mouse models ofpsoriasis, specifically, the imiquimod (IMQ)-treated mouse model (See DiMeglio et al., (2014) Immunity, 40(6): 989-1001, and Smith et al, (2017)J Invest Dermatol, 137(10), 2110-2119). The biological activity ofcompounds of Formula (I) were tested in this mouse model for evidence ofanti-inflammatory activity in vivo.

Female BALB/c mice (BALB/cByJRj) were purchased from Janvier (France).Mice are allowed to eat a normal diet A04C from SAFE (France) and drinkad libitum. BALB/c JByRj female mice (8 week-old at study initiation)are treated with imiquimod (IMQ) cream (5%) or vanicream(non-inflammatory inert cream). For three days of pre-treatment, andthen daily until the end of the study (two hours before each applicationof IMQ), the same skin area is treated topically with 100 μL, ofcompound. Mice are monitored for changes in clinical symptoms over thecourse of the study. Affected back skin is examined by histology andqPCR for evidence of compound efficacy.

The biological activity of the compounds of Formula (I), as representedby 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, was tested in thismouse model for evidence of anti-inflammatory activity in vivo. Skinhistological analysis demonstrated that was able to reduce the epidermisthickening induced by imiquimod. Skin gene expression data revealedIL-17A and IL-17F expression was significantly inhibited by thecompound.

Example 9: Mechanism of Compounds of the Invention as AhR Agonist andSimilarity to Tapinarof

Tapinarof is a first in class topical medicine under development totreat atopic dermatitis and psoriasis. The biological profile oftapinarof differs from other anti-inflammatory and immunomodulatorymolecules currently used in the treatment of inflammatory skin diseases,including TCSs, TCIs, vitamin D analogs, and other immunosuppressiveagents. All data currently available indicates that tapinarof exerts itspharmacological action in the skin via a novel mechanism involving dualactivation of AhR and Nrf2 anti-inflammatory pathways, therebyidentifying tapinarof as a therapeutic AhR-modulating agent (TAMA).Tapinarof demonstrated specific inhibition of pro-inflammatorymediators, including interleukin [IL]-6, IL-17A, and eotaxin-3, whichmay be downstream of AhR pathway activation. In addition, treatment withtapinarof reduces reactive oxygen species (ROS) in chemicallyredox-stressed keratinocytes, and induces cellular apoptosis in themicromolar range.

A direct mechanistic link between AhR and anti-inflammatory activity hasnot been fully elucidated, nor has the means to identify a safe TAMAwhile other compounds might drive AhR-mediated liabilities, beenconclusively determined. Therefore,2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, was assessed for eachof tapinarof's known activities. A summary of this mechanistic work isprovided below.

2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, was evaluated foractivity in the primary ‘hits’ identified in tapinarof's mechanisticstudies (Table 3). Indeed,2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, exhibited similarpotency across each of AhR, Nrf2 and CB2 screening assays, as well as inIL-17A inhibition in CD4+ T cells cultured under Th17-polarizingconditions.

TABLE 3 Primary screen comparison of2-isopropyl-5-(isoquinolin-3-yl)benzene- 1,3-diol, to the clinical leadtapinarof 2-isopropyl- 5- (isoquinolin- 3- yl)benzene- Target AssayDescription tapinarof 1,3-diol, AhR fluorescence-based reporter assaypEC₅₀ = 7.9 pEC₅₀ = 7.8 for CYP1A1 gene expression Nrf2 luciferase-basedreporter assay for pEC₅₀ = 7.6 pEC₅₀ = 7.0 NQO1 gene expression CB2fluorescence-based agonist assay pEC₅₀ = 6.8 pEC₅₀ = 6.7 usinggenetically modified yeast IL-17A MSD-based readout of secreted pIC₅₀ =8.5 pIC₅₀ = 8.4 IL-17A from Th17-polarized primary human CD4+ peripheralblood T cells

Example 10: BioMAP Profiling of2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol

2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was profiled atmultiple doses, 1 μM, 330 nM, 110 nM and 37 nM, using the DiscoveRxBioMAP® Diversity Plus System™. The BioMAP System evaluates 148biomarkers relevant to multiple inflammatory diseases across 12different primary human cell culture platforms, and compares thebiomarker profile to patterns of biological responses of othercompounds, biologics and approved drugs from the BioMAP referencedatabase of >3000 experimental agents. Of the analytes tested2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (was found to beanti-proliferative to B cells, led to reductions in variouscytokines/chemokines, including M-CSF, sIL-17A, sIL-2, sIL-6, sIL-10,Eot3, sTNFα, MCP-1, VCAM-1, and MIP-1, and increased IL8, IL1α, sPGE₂,ICAM-1, and E-selectin (FIGS. 1A-1G). Similar to tapinarof, theendogenous AhR agonist, 6-formylindolo(3,2-b)carbazole (FICZ), was theonly compound identified from the BioMAP reference database with arelated pattern of biological responses (Pearson correlation, r=0.71;FIGS. 1H-1N). Likewise, marked similarities to tapinarof are noted whenthe profiles are overlaid (FIGS. 1O-1U). The most striking difference isan observed reduction in sIL-17 by2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, that is not seen intapinarof or FICZ-treated samples.

Example 11: Impact of 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol,on Cytokine and Cellular Apoptosis

The impact of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol treatmenton peripheral blood CD4+ T cells cultured under Th17-skewing conditionswas evaluated. When applied throughout the culture period,2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, reduces IL-17Aproduction in a dose-dependent manner, similar to tapinarof (FIG. 2A).

2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol impacts T cellviability with an IC₅₀=5.9 μM, and keratinocyte viability with anIC₅₀=12.36 μM. These values are similar to that of tapinarof and supportthe notion that 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol is aclose phenocopy of tapinarof's activity profile (FIG. 2B, FIG. 2C).

Example 12: Inhibition of Reactive Oxygen Species (ROS) by2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol

Tapinarof was observed to suppress chemically-induced ROS in primary andimmortalized (HaCat) keratinocytes, resulting at least in part fromintrinsic ROS scavaging properties of the API (Smith et al., 2017,ibid). Importantly, the observed reduction in ROS is a keydifferentiator between tapinarof and TCDD, a known environmental toxinthat leads to increased ROS levels. Therefore,2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was tested for itsability to reduce ROS. Using the oxygen radical absorbance capacity(ORAC) test, tapinarof was shown to scavenge peroxinitrite, superoxideanions, singlet oxygen, peroxyl radicals and hydroxyl radicals, allcommon species of ROS. 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diolexhibited a similar profile, reducing levels of peroxinitrite, singletoxygen, peroxyl radicals and hydroxyl radicals (Table 4).

TABLE 4 Oxygen Radical Absorbance Capacity (ORAC), measured in TroloxEquivalent Values (TEV) Peroxyl Peroxyl Total Superoxide Singletradical- radical- Hydroxyl- ORAC ID Peroxynitrite anion oxygen hydrolipo radical value 2-isopropyl-5- 100 ND 2914 3267 1397 759 8437(isoquinolin- 3-yl)benzene- 1,3-diol tapinarof 140 11241 3581 4663 21641067 22855

Example 13: Demonstration of Biological Activity (Target Engagement)Following Topical Delivery

A liquid-air interface skin explant culture with the in situ activationof immunocompetent cells, termed sRICA for skin-Resident Immune CellActivation model was previously reported (Smith et al., (2016) PLoS One,11(2)). In this assay, specific cytokine profiles of inflammatory skindiseases can be induced, including the Th17-type cytokines, IL17A, IL17Fand IL22. Reduction of biomarkers in this assay indicates biologicalactivity of the test compound.

Ex vivo human skin obtained from abdominoplasty surgery was processed toremove fat and dermatomed the tissue to ˜750 microns. Dermatomed skinwas then cleaned in two serial rinses of 5-10 minutes each in roomtemperature PBS containing an antibiotic/antimycotic solution.

Skin was treated as asceptic from this point on; all furthermanipulations were performed in a class II biosafety cabinet. The skinsection was cut with disposable single-use biopsy punches to 10 mmdiameter round sections, which were then placed in the upper chamber ofa 0.4 um PCF membrane transwell (Millicell #PIHP01250) containing 30 μLof a bovine collagen solution (2:1 collagen/corni media). Care was takento remove any bubbles under the transwell as they would inhibit thepermeation of the media into the tissue.

The skin samples were allowed to set on the collagen solution for 30 minat 37° C. in a humidified chamber. After a 30 minute incubation at 37°C., which allows the collagen solution time to set, skin samples ontranswells were transferred to 6-well plates (1 sample per well) and thelower chamber filled with 1 mL complete media (Cornification Media)+/−2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (0 uM, 1 uM, or 10uM) and allowed to rest overnight (16-18 h) at 37° C.

The next day, media was aspirated from the lower chamber, replaced with1 mL complete media containing Th17 cocktail (CD3 (1 ug/ml), CD28 (2ug/ml), anti-IL-4 (1 ug/ml), anti-INFg (1 ug/ml), IL-1b (10 ng/ml), IL-6(10 ng/ml), TGFb (1 ng/ml), IL-21 (10 ng/ml)) incubated for 24 hours and48 hours. A total of 3 biological replicates were used for eachtreatment group.

Cultures were harvested at 24 hrs and 48 hrs post-stimulation. Uponharvest, skin samples were minced with a razor blade and transferred to1.5 mL RNAse-free tubes with 1 mL RNAlater solution until later analysisby RT-PCR.

RNA Isolation and qRT-PCR

The harvested skin tissue were stored in RNA later until use. Total RNAwas isolated from the tissue with Qiagen's Mini RNA Isolation kit (Cat#74106). Skin tissue were first minced to less than 1×1×1 mm pieces,then added to tube containing 2.8 and 1.4 mm ceramic beads (mixed intoone vial). Cells were lysed in 300 μL of RLT buffer supplemented with 1%2-Beta-Mercapto-Ethanol in Precellys Tissue Homogenizer performed for 4cycles (6300 rpm 90s) and on ice for 30s between each cycle. Then, 590μL of water containing 10 μL Proteinase K was added to the lysed cellsand incubated at 55° C. for 20 minutes. Samples were then spun down for3 minutes at 10,000×g and the supernantant was used for RNA isolationusing Qiagen's RNeasy mini columns according to manufacturer's protocol.RNA was diluted to a concentration of 23.6 ng/ul (total of 100 ng RNA),and was used as template in a 10 uL PCR volume using Applied BiosciencesRNA-to-CT 1 Step kit (AB Catalog #4392938) and the specific TaqManprobes foreach gene to be quantified. Applied Biosciences' Master Mixhas a ROX dye internal control. A OneStepPlus PCR machine was used forboth the RT step and the 40 amplification cycles.

RNA levels of gene of interest's Relative Expression was calculatedusing the Delta Delta CT formula.

$\frac{X_{test}}{X_{con{trol}}} = {{{\,_{2}{\Delta\Delta}}C_{T}} = {{{\,_{2}\Delta}C_{T,{control}}} - {\Delta C_{T,{test}}}}}$

RNA was isolated from the tissue harvested at 24 hr and 48 hr poststimulation and gene expression was assessed by quantitative PCR. Dataand statistical analysis was performed with Microsoft Excel 7 and PrismGraphPad 6.

Engagement of the target pathway by2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, in this case AhRpathway activation as measured by cyp1a1 gene induction, was confirmedfollowing exposure of skin explants to 1 μM or 10 μM2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in the baso-lateralmedia (FIG. 3A). Next, the impact on inflammatory mediators wasassessed, demonstrating that 10 μM of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol inhibits IL17A messageexpression by ˜45% (FIG. 3B). In this study, the RORg inverse agonistcompound GSK3038548A was used as a positive control for inhibition ofIl17a gene expression.

The sRICA model was adapted to the Franz cell apparatus to demonstratetwo specific outcomes for topical delivery: (i) that the test compoundremains biologically active in its formulation, and (ii) that the testcompound can penetrate the skin barrier to reach its dermal target andelicit a biological effect. Topical target engagement of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was assessed in creamformulation 1 and gel formulation 1 at multiple concentrations.Importantly, because these target engagement assays utilize customizedFranz cells that clamp the edges of the skin, leakage of topicalformulations into the lower chamber of the air-liquid interface cultureis prevented. Cyp1a1 gene expression was used as an indicator of AhRpathway activation. As such, no activation of skin resident immune cellsunder Th17 conditions was performed, as typical for the Th17-sRICAdescribed above. Rather, 12 mm skin sections were clamped between upper(donor) and lower (receiving) chamber of customized Franz cells, thenthe lower chamber was filled with 2.0 mL complete media (“Corni”), suchthat the baso-lateral surface was bathed in media and no air bubbleswere present. Following a ˜2 hour rest period at 37° C., cells werechecked again for leakage by simple inversion and then topicalformulation (8.4 μl) was applied to the dry stratum cornium using apositive displacement pipette. Franz cells were then placed in a 37° C.humidified incubator for an additional 21 hours. Cyp1a1 levels wereassessed, relative to baso-laterally applied2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (10 μM) in roughly ½ ofeach skin section, while the other half was used to determine2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol concentration. Samplescontaining at least 0.1%2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in the creamformulation 1 exhibited strong cyp1a1 gene induction, with no observabledose dependency (FIG. 4 ). This data show that the maximum observablebiological response is induced with the lowest formulated concentrationin this system.

Example 14: In Vivo Efficacy in Mouse Models

Targeting the AhR pathway with systemic FICZ treatment has beendemonstrated to positively impact clinical scores of imiquimod(IMQ)-treated mice (Di Meglio et al., (2014) ibid). Further, tapinarofexhibits anti-inflammatory properties in multiple mouse models,including an ear eczema model, the IMQ mouse model of psoriasis and theDNFB-challenge model, which is a hapten-induced, Th2-dominant challengemodel. 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was also testedin two mouse models of inflammation: the IMQ and DNFB mouse models.

IMQ Mouse Model

2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was tested in the IMQmouse model in a preventative manner, with daily topical application of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in a simple ethanolicsolution (60% EtOH: 40% H₂O). Starting 3 days after first treatment, IMQcream was applied daily for 4 (Study A) or 10 days (Study B). Clinicalscoring was monitored daily (FIGS. 5A to 5D). At the end of the study,treated skin was evaluated by histology and qPCR for induced cytokinegene expression. 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-dioltreatment led to reduced clinical score, reduced epidermal thickeningand reduced cytokine gene expression as compared to vehicle-treated mice(N=10 mice per arm, FIGS. 5A to 5D and Table 5).

Study A

Three groups of ten mice (BALB/cByJRJ Female Mice) were treated asfollows: Days −3, −2 −1 (three days before imiquimod application) anddays 0, 1, 2, 3 (4 day study): The shaved backs of the mice were treateddaily with either vehicle (100 μL of 60% EtOH/40% water) or2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (0.3% in 60% EtOH/40%water). On days 0, 1, 2, 3 a daily topical application of vanicream or5% imiquimod cream (5% Aldara cream) was applied to the shaved back 2hours after 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol or vehicleapplication and massaged with a finger until absorbed. On days 0, 1, 2,3: visual evaluation of the skin and psoriasis clinical score werenoted.

Psoriasis reactions (erythema and plaques) are reported according to a0-4 scale in ascending order of severity as shown below and results areshown in FIG. 5A.

Psoriasis score Grade No reaction-Normal 0 Slight erythema 1 Moderate tosevere erythema and some plaques 2 Marked erythema and plaques 3 Verymarked erythema and plaques 4

On the last day of treatment, a 6 mm punch of skin in the treated areais collected on a aluminium sheet (to keep the skin flattened) andplaced into a tube containing Formalin solution (Neutral Buffered 10%(SIGMA HT501320-9 5L)) for histological analysis (FIG. 5B).

Study B

Four groups of ten mice (BALB/cByJRJ Female Mice) were treated asfollows: Days −3, −2 −1 (three days before imiquimod application) anddays 0, 1, 2, 3, 5, 6, 7, 8, 9, (10 day study): The shaved backs of themice were treated daily with either vehicle (100 μL of 60% EtOH/40%water), 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (0.1% in 60%EtOH/40% water) or 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol(0.3% in 60% EtOH/40% water). On days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 adaily topical application of vanicream or 5% imiquimod cream (5% Aldaracream) was applied to the shaved back 2 hours after2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol or vehicle applicationand massaged with a finger until absorbed. On days 0, 1, 2, 3, 4, 5, 6,7, 8, 9: visual evaluation of the skin and psoriasis clinical score werenoted.

Psoriasis reactions (erythema and plaques) are reported according to a0-4 scale in ascending order of severity as shown below and results areshown in FIG. 5C.

Psoriasis score Grade No reaction-Normal 0 Slight erythema 1 Moderate tosevere erythema and some plaques 2 Marked erythema and plaques 3 Verymarked erythema and plaques 4

On the last day of treatment, a 6 mm punch of skin in the treated areais collected on a aluminium sheet (to keep the skin flattened) andplaced into a tube containing Formalin solution (Neutral Buffered 10%(SIGMA HT501320-9 5L)) for histological analysis (FIG. 5D).

In a separate study (Study C),2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in a cream formulation1 was re-tested in the IMQ mouse model. In this last study, excessiveredness was induced by IMQ in all treatment arms, resulting in noobserved change to clinical score with compound treatment. Nonetheless,a reduction in epidermal thickness was observed when2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was applied in creamformulation 1 (FIGS. 5A to 5F), as well as significant reductions inIL17A and IL17F levels (>80% at the highest dose tested).

TABLE 5 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol reduced IL-17Aand IL-17F tissue mRNA expression in the imiquimod mouse model ofpsoriasis (Study A - corresponding to FIG. 5A, Study B - correspondingto FIG. 5B) IL-17% effect vs. IL-17F % effect vs Study # Treatment IMQ +SEM IMQ + SEM Study A Vehicle + IMQ   100 + 15.055   100 + 13.7242-isopropy1-5- 16.27 + 4.816 22.21 + 7.418 (isoquinolin-3-yl)benzene-1,3-diol (0.3%) + IMQ Study B Vehicle + IMQ   100 + 47.848  100 + 53.188 2-isopropy1-5- 78.48 + 18.771 45.23 + 9.519(isoquinolin-3- yl)benzene-1,3-diol (0.1%) + IMQ 2-isopropyl-5- 79.33 +22.900 60.01 + 12.229 (isoquinolin-3- yl)benzene-1,3-diol (0.3%) + IMQ

DNFB Mouse Model

2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was next tested in thedinitrofluorobenzene (DNFB) mouse model (See FIGS. 6A to 6E). DNFB is asmall chemical hapten that induces a delayed-type hypersensitivityreaction with some similarity to human atopic dermatitis. As with theIMQ challenge studies, 0.3%2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was first tested in asimple ethanolic formulation, demonstrating 20% and 34% reductions inepidermal and dermal thickness, respectively, when applied twice daily(FIGS. 6B to 6C). The effect is not observed in a second study where2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was formulated in creamformulation 1 and applied only once per day throughout the study (FIGS.6D to 6E). This may indicate reduced exposure to the compound in thesecond study, although additional data would be required to understandwhether this discrepancy results from different dosing strategies (q.d.vs b.i.d.), limitations of cream formulation 1, or another reason.Nonetheless, taken together with results from the IMQ mouse model, thedata indicate that 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol isanticipated to have broad anti-inflammatory activity that would bebeneficial to both atopic dermatitis and psoriasis patients.

Second Study

Healthy female CDl mice (Crl:CDl (ICR)) were shaved on the abdomen andthe nape of the neck under a 3 to 5% isoflurane anesthesia.

After body weight measurement, animals were allocated to study groups,according to the treatment table below. The study was divided in twoarms, separated by 1 week, in order to accommodate for the in lifemonitoring of scratching monitoring. Half of the animals from each group(6 mice) were allocated in arm 1 and arm 2 respectively.

Group # of Animals Treatment 1 12 Acetone/Olive Oil Vehicle (60% EtOH,40% water) 2 12 DNFB (0.15% in Acetone/Olive Oil) Vehicle (60% EtOH, 40%water) 3 12 DNFB (0.15% in Acetone/Olive Oil) 0% Cream Formulation 1 412 DNFB (0.15% in Acetone/Olive Oil) 0.3% Cream Formulation 1 5 12 DNFB(0.15% in Acetone/Olive Oil) 0.05% Clobetasol cream

For each topical treatment, 100 mg of cream or 100 μL of liquidformulation were applied on the mouse nape of the neck skin using asolvent pipette. When creams were used, they were spread with a fingerand allowed to penetrate the skin by massage until complete absorption.

On Day 1, a topical application of acetone/olive oil (4:1 vol:vol) or0.15% DNFB (2,4 Dinitrofluorobenzenzene in acetone/olive oil (4:1vol:vol) was performed on the shaved abdomen under a volume of 100 μL(sensitization phase). On Days 5, 8, 12 and 15, 100 μL of acetone/oliveoil or 0.15% DNFB were applied topically on the shaved nape of the neckskin (elicitation phase). From Days 5 to Day 17, 100 mg of 0.3% creamformulation 1 (group 4), 0% cream formulation 1 (group 3, placebo cream)or 100 mg of 0.05% Clobetasol cream (group 5) were applied once daily onthe nape of the neck, 2 hours before the DNFB challenge.

Mice were culled on Day 17 under a 3 to 5% isoflurane anesthesia, 4hours after the last topical treatment, and 48 hours after the last DNFBor acetone/olive oil challenge. Nape of the neck skin samples werecollected for histological analyses in formalin solution, 10% neutralbuffered. Epidermal (FIG. 6D) and dermal thickness (FIG. 6E) weremeasured.

Example 15: In Vitro Human Skin Penetration Evaluation

The in vitro human skin penetration and distribution of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was assessed using acustom-made (ChanneL) flow-through diffusion cell setup and ex vivohuman skin (from abdominoplasty surgery) dermatomed at 500±100 μm. Theskin distribution (epidermis and dermis) and cumulative amount in thereceiving fluid (representative of unbound drug penetrating below 500μm) over 16 hours was evaluated using a fit-for-purpose LC-MS/MS methodwith a lower limit of quantification (LLOQ) of 80 pg/mL to determine thedermal delivery profile of the formulation prototypes. The biologicaltarget for 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was theepidermis/upper dermis, and the formulation ranking focused on thedermis levels due to the low cumulative amounts in the receiving fluid.Epidermis samples may still contain residual drug that did not penetratethe stratum corneum, and therefore were not considered for rankingpurposes.

During the initial formulation development stage, eight topicalformulations (6 creams and 2 gels) loaded with 1.0%2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol were evaluated in thein vitro human skin penetration assay using three donors. The deliveryof 2-isopropyl-5- (isoquinolin-3-yl)benzene-1,3-diol into the epidermisand dermis at 16 hours is shown in FIG. 7 . The amounts delivered to thedermis ranged between 0.4 and 2.6 μg, and only low cumulative amounts(less than 20 ng over 16 hours, FIG. 8 ) were quantified in thereceiving fluid.

The statistical significance of the dermis amounts was evaluated usingStudent's t-test, and presented in a way that formulations not connectedby the same letter (“A” to “C”) are statistically different (p<0.05,Table 6). The formulations 1% cream formulation 3 and 1% gel formulation4 delivered higher amounts of drug to the dermis.

TABLE 6 Statistical Evaluation of2-Isopropyl-5-(isoquinolin-3-yl)benzene- 1,3-diol Formulations by AmountDelivered to the Dermis (μg). Formulation 2-Isopropyl-5- Dermis amount(pg) (isoquinolin-3-yl)benzene- Standard error of the 1,3-diol t-testMean mean 1% cream formulation 3 A 2.62 0.38 1% gel formulation 4 A 2.520.60 1% cream formulation 4 A B C 2.13 0.40 1% cream formulation 7 A B C2.03 0.38 1% gel forumlation 3 A B C 1.78 0.52 1% cream formulation 2 AB C 1.69 0.34 1% cream formulation 6 B C 1.04 0.20 1% cream formulation5 C 0.36 0.06

Additionally, due to improved physical stability, the cream formulation2 and a similar formulation with lower transcutol P level, creamformulation 1, were also progressed to the dose proportionality study.Based on the dermis amounts shown in FIG. 9 , 1% cream formulation 3 and1% cream formulation 1 yielded the best dose proportionality, with thelatter exhibiting comparable delivery to the dermis and improvedstability profile.

To further evaluate the potential for a2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol gel (specifically onewith an amount of propylene glycol below 15%), two more formulatons (gelformulation 1 and gel formulation 2) were evaluated in the in vitro skinpenetration assay. No gel delivered significantly more2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol to the dermis than anyof the other test articles (FIG. 10 ). Cumulative amounts were measuredbut not considered in the ranking (FIG. 11 ).

Matrix-assisted laser desorption ionization imaging mass spectrometry(MALDI IMS) was also used to demonstrate spatial localization of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol within the skin layers.The 1% cream formulation 1 was selected for this study, in addition to0.5% cream formulation 3 and 1% gel formulation 4; these prototypesdelivered equivalent amounts of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol to the dermis duringthe dose proportionality study. A single dose of the three formulationswas applied to human full-thickness skin and samples were collected at 6and 24 hours. Following collection and preparation, samples were sentfor MALDI. At six hours (Table 7), the amount of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol delivered to the levelof the dermis is 5.0 to 7.0 fold higher for the 1% gel formulation 4compared to the 0.5% cream formulation 3 and 1% cream formulation 1;however, after 24 hours this difference was approximately 2.0-fold.

The drug concentrations from the in vitro human skin penetration and theMALDI IMS studies were compared and results presented in Table 7. A fewassumptions were made to calculate the concentrations in eachcompartment using data from the skin penetration assay: (i) the volumeof each compartment was calculated using a dosing area of 1 cm²; (ii)the skin thickness for epidermis and dermis was estimated to be 150 μmand 350 μ, respectively, (iii) the drug distribution was assumed to behomogeneous within each compartment, and (iv) the tissue density wasassumed to be 1 g/mL. The concentrations did not account for drugfraction bound or unbound.

The concentrations observed in the epidermis for the two creams were onaverage 2.4-fold higher in the 16 hour in vitro human skin penetrationstudy than at the 6 hour MALDI time point; however, the epidermisamounts delivered by the gel in the 6 hour MALDI study were comparableto those in the in vitro skin penetration assay. At the 24 hour MALDItime point the epidermis amounts for the gel formulation have decreased,making the values from the in vitro skin penetration study 1.5-foldhigher in comparison. The creams do not exhibit this behavior, butinstead show epidermis amounts increasing from 6 hours to 24 hours, andbecoming comparable to the amounts delivered in the in vitro skinpenetration study. This difference in behavior suggests a disparity inthe formulation delivery kinetics between the gel and creamformulations. A comparison of the dermis values shows that 3.0 to6.5-fold higher amounts of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol were delivered in the invitro human skin penetration assay (16 hours) than in the MALDIexperiment (24 hours). These variations between the concentrations canbe attributed to the differences in study protocols used across the twoassays, including skin thickness, skin donors and analytical methods.

TABLE 7 Calculated Skin Concentrations (μM and μg/g) in the Epidermisand Dermis Compartments (± SEM, when shown) In vitro human skinpenetration MALDI-IMS MALDI-IMS (16 hours, n = 15-18) (6 hours, n = **)(24 hours, n = **) Epidermis μM Dermis μM Epidermis μM Dermis μMEpidermis μM Dermis μM Formulation [μg/g] [μg/g] [μg/g] [μg/g] [μg/g][μg/g] 1% cream 1188.4 ± 287.4 180.2 ± 52.3  442.7 ± 6.1 14.0 ± 1.8 1448.2 ± 13.6 28.3 ± 1.7  formulation 1 [332.0 ± 80.3] [50.3 ± 14.6][123.7 ± 1.7] [3.9 ± 0.5] [404.5 ± 3.8] [7.9 ± 0.5] 0.5% cream 1090.0 ±229.9 184.1 ± 47.6  533.5 ± 4.8 9.7 ± 1.6 1024.0 ± 12.6 32.7 ± 1.3 formulation 3 [304.5 ± 64.2] [51.4 ± 13.3] [149.0 ± 1.3] [2.7 ± 0.5][286.0 ± 3.5] [9.1 ± 0.4] 1.0% gel 4258.0 ± 638.2 201.4 ± 24.2  5492.7 ±64.3 71.9 ± 2.2  2768.2 ± 38.8 66.8 ± 1.3  formulation 4 [1189.4 ±178.3] [56.3 ± 6.8]  [1534.3 ± 18.0] [20.1 ± 0.6]   [773.3 ± 10.8] [18.7± 0.4]  ** Values reported for the MALDI-IMS analysis of ex vivo humanskin are the average of 6 skin sections, taken from 2 skin penetrationreplicates (3 sections per skin replicate), using 1 skin donor

Example 16: Absorption, Distribution, Metabolism, and Excretion

2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol showed high binding toplasma proteins and the unbound fraction values at 2 μM were 3.06%,1.98% and 1.08% in rat, minipig and human, respectively (Table 8). Theskin binding of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol inwhole human skin, epidermis and dermis homogenate was tested at threeconcentrations (25, 50 and 100 ng/mL, respectively 0.089, 0.179 and0.358 μM) and showed a mean unbound fraction value of 21.9±0.72%,51.3±1.1% and 34.1±11.5%. The blood-to-plasma ratios were similar acrossspecies (1.22-1.36, Table 9).2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was stable in plasmaand blood.

TABLE 8 Binding of 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3- diol (2μM) in Rat, Minipig and Human Plasma Proteins as Determined by RapidEquilibrium Dialysis (RED) Device % Unbound Mean % Mean % Stability Mean% Species Replicate (% CV) Bound at 4 hrs Recovery Rat 1.37 1.44 6.363.06 (93.6) 96.9 94.4 104 Minipig 1.87 2.52 1.57 1.98 (24.6) 98.0 10795.6 Human 1.06 1.05 1.13 1.08 (3.71) 98.9 101 102

TABLE 9 The Blood-to-plasma Ratio and Extent of Association of2-Isopropyl-5- (isoquinolin-3-yl)benzene-1,3-diol (1 μM) with BloodCells in Rat, Minipig and Human Blood-to-plasma Ratio % Blood CellAssociation Mean % Mean Mean Blood Species Replicate (% CV) Replicate (%CV) Stability Rat 1.31 1.29 1.46 1.36 (6.83) 58.9 58.3 63.1 60.2 (4.37)104 Minipig 1.21 1.25 1.19 1.22 (2.54) 55.3 56.8 54.5 55.6 (2.02) 105Human 1.21 1.29 1.23 1.24 (2.95) 53.9 56.4 54.6 55.0 (2.39) 107

2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was rapidly metabolizedby liver microsomes and/or hepatocytes across species; mouse, rat,minipig, dog, rabbit and human, suggesting high intrinsic in vitroclearance. The intrinsic metabolic clearance in hepatocytes was 2.1 to11.6-fold greater than the intrinsic clearance in liver microsomesacross rat, minipig and human (Table 10), and it correlated well withthe in vivo clearance (see below: Animal Pharmacokinetics) measured inrat and minipig pharmacokinetic studies with in vitro-to-in vivoextrapolation (IVIVE) ratios of 0.45 for rat and 0.27 for minipig.

TABLE 10 The Metabolic Stability of2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (0.5 μM) in LiverMicrosomes and Hepatocytes in Mouse, Rat, Minipig, Dog, Rabbit and HumanLiver Liver Microsomes Hepatocytes Weight CLint,mic Half- ScaledCLint,hep Half- Scaled (g (mL/min/g life CLint,mic (mL/min/g lifeCLint,hep Species liver/kg) liver) (min) (mL/min/kg) liver) (min)(mL/min/kg) Mouse 51 23.4 2.84 1194 22.3 8.39 1137 Rat 36 6.21 10.3 22444.4 3.37 1597 Minipig 16.7 3.01 24.2 50.3 6.27 26.5 105 Dog 32.5 1.5932.1 51.7 7.39 31.9 240 Rabbit 30.8 11.9 6.10 367 7.80 21.3 240 Human24.5 1.35 40.9 33.1 15.7 10.4 384

The in vitro GSH-trapping assay detected reactive metabolites for2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol following 1 hourincubation in human or rat liver microsomes supplemented withglutathione (GSH) and glutathione ethyl-ester (GSEE, Table 11). Theseresults suggest that there is a potential for2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol to form reactivemetabolites. Despite these findings,2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol is not expected to posea safety risk due to the low systemic exposure in vivo following topicaladministration in rat and minipig (see Animal Pharmacokinetics sectionbelow) and estimated low plasma concentration in human (see Estimationof Human Plasma Concentration section below).

TABLE 11 Detection of GSH Trapped Reactive Metabolites of 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (10 μM) in Liver Microsomes P + O +GSH P + O + GSH − 2H P + GSH P + GSH − 2H Species (+323 Da) (+321 Da)(+307 Da) (+305 Da) Rat + + − + Human − + − + P = Parent; O = Oxygen;GSH = Glutathione

Example 17: Animal Pharmacokinetics

The preclinical pharmacokinetic profiles of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol were characterized byhigh clearance and high volume of distribution with short half-life inrat and minipig (Table 12, FIG. 12 ). Following subcutaneousadministration in rat, the pharmacokinetics of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in plasma were roughlylinear between 10 and 25 mg/kg with both 30% Captisol and 30% Cavitronformulations. The 30% Captisol formulation achieved similar (<17%)plasma exposure (AUC_(24h)), whereas C_(max) was 3.2 to 4.1 fold higher,compared to the 30% Cavitron formulation (Table 13). Bioavailability was46.5% and 41.0% for 30% Captisol and 30% Cavitron, respectively. 30%Captisol formulation was selected for the 7-day subcutaneous toxicitystudy in rat. The bioavailability in minipig following a single 5 mg/kgoral dose with DMSO: Kolliphore HS15: hydroxypropyl-β-cyclodextrin(10:10:80) vehicle was 0.1%, suggesting that the oral route was notsuitable for systemic safety assessment in minipig.

TABLE 12 Pharmacokinetics of2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol After a SingleIntravenous Dose in Rat and Minipig. Dose AUC_(∞) Species (mg/kg) CL_(p)(mL/min/kg) V_(ss) (L/kg) T_(1/2) (hr) (ng * hr/mL) Rat 1 175.2 (±16.4)6.0 (±2.6) 0.69 (±0.17) 95.7 (±9.3) Minipig 1  21.3 (21.5, 20.8) 1.5(1.95, 1.04) 1.02 (1.4, 0.7)  783 (766, 800) Note: Mean (±SD), n = 3 forrat and mean (individual) for minipig

TABLE 13 Effect of Dose and Formulation on2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol Pharmacokinetics AfterSubcutaneous Administration in Rat C_(max)/Dose AUC_(24 h)/Dose DoseC_(max) ng/mL per T_(max) AUC_(24 h) ng * hr/mL per Formulation mg/kgng/mL mg/kg hour ng * hr/mL mg/kg F % 30% Captisol 10  239 (±16.2) 23.9(±1.6)   0.4 (±0.1)  437 (±28.8) 43.7 (±2.9) 45.9 (±2.9) 25  661 (±111) 26.4 (±4.4)  0.25 (±0)   1123 (±413)  44.9 (±17)  47.1 (±17)  30%Cavitron 10 73.9 (±6.6)   7.4 (±0.66)  1.8 (±1.9) 385 (±90)  38.5 (±9.0)41.3 (±10)  25  162 (±20.4)  6.5 (±0.82)  2.4 (±3.1)  960 (±148)  38.4(±5.6) 40.7 (±5.8) Note: Mean (±SD) n = 3

Following a single 20 mg (of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol)/kg topicaladministration with 10% body surface area (BSA) coverage in rats,2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol exhibited comparableplasma exposure between 1% cream formulation 1 (C_(max) 3.83 ng/mL andAUC_(24h) 32.1 ng*hr/mL) and 1% gel formulation 1 (C_(max) 5.18 ng/mLand AUC_(24h) 46.0 ng*hr/mL) formulations. Bioavailability was very low;1.7% for 1% cream formulation 1 and 2.4% for 1% gel formulation 1 (Table14). Similarly, very low plasma exposure (87% of time points below lowerlimit of quantification, 50 pg/mL) was observed in minipig following asingle 15 mg (of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol)/kgtopical dose in 1% cream formulation 1 or 1% gel formulation 1 with 10%body surface area coverage, suggesting low systemic safety riskfollowing topical administration.

TABLE 14 Plasma Pharmacokinetics of2-Isopropyl-5-(Isoquinolin-3-yl)benzene-1,3-diol BSA in RatAUC_(24 h)/dose Dose Dose Area C_(max) T_(max) AUC_(24 h) ng * hr/mLFormulation mg/kg cm² ng/mL hour ng * hr/mL per mg/kg F % 1% cream 2040.2 (±0.37) 3.83 (±1.82) 4.0 (±1.6) 32.1 (±37.3) 1.6 (±1.9) 1.7 (±1.9)form. 1 1% gel 20 39.8 (±1.08) 5.18 (±1.92) 2.6 (±1.8) 46.0 (±14.7) 2.3(±0.7) 2.4 (±0.7) form. 1 Note: Mean (±SD) n = 4

Skin pharmacokinetics of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was investigated inGottingen minipig for 7 days following a single topical administrationof 1% cream formulation 1 or 1% gel formulation 1. The formulations wereadministered at a dose rate of 1 g of formulation/44 cm², and skinbiopsies were collected at different time points up to 168 hours forpharmacokinetics (tissue homogenate levels in epidermis and dermis) andMALDI IMS (matrix-assisted laser desorption ionization imaging massspectrometry) analysis. Higher concentrations of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol were noted in theepidermis/upper dermis (0-500 μm) compared to the dermis (500-1500 μm)for both formulations (Table 15, FIG. 13 ). The 1% cream formulation 1achieved similar epidermis/upper dermis (C_(max) 23.4 μg/g andAUC_(168h) 2026 μg*hr/mL) and dermis (C_(max) 0.74 μg/g and AUC_(168h)37.5 μg*hr/mL) exposures compared to that observed for the 1% gelformulation 1: epidermis (C_(max) 18.0 μg/g and AUC_(168h) 1729μg*hr/mL) and dermis (C_(max) 0.39 μg/g and AUC_(168h) 34.7 μg*hr/mL).Depth profiling by MALDI IMS for one minipig from each group atdifferent time points showed consistency with pharmacokinetic data: themaximum concentration observed in the epidermis (0-100 μm) and upperdermis (100-500 μm) for 1% cream formulation 1 were 9.4 μg/g at 48 hoursand 1.37 μg/g at 72 hours; for 1% gel formulation 1 these wererespectively 21.8 μg/g and 1.66 μg/g at 8 hours (Table 16). Some of theMALDI images for 1% cream formulation 1 (e.g. 8 hours) and 1% gelformulation 1 (e.g. 48 hours) also showed drug penetration via the hairfollicles, suggesting that the skin appendage route may contribute tosystemic exposure (FIG. 12 ). MALDI IMS signal dropped to below thelimit of detection (approximately 500 ng/g) by around 500 μm depth.

TABLE 15 Skin Pharmacokinetics of2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol Following a SingleTopical Administration (1 g of Formulation/44 cm²) in MinipigEpidermis/Upper Dermis (0-500 μm) Dermis (500-1500 μm) Animal C_(max)AUC_(168 h) T_(max) C_(max) AUC_(168 h) T_(max) Formulation ID (μg/g)(μg * hr/g) (hr) (μg/g) (μg * hr/g) (hr) 1% cream S0001 19.2 1659 480.55 36.7 72 formulation 1 S0002 27.5 2394 72 0.92 38.3 72 Mean 23.42026 60 0.74 37.5 72 1% gel S0101 23.9 2401 8 0.43 38.4 168 formulation1 S0102 12.0 1056 48 0.35 31.0 48 Mean 18.0 1729 28 0.39 34.7 108

TABLE 16 Skin Levels of 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diolDetermined by MALDI IMS in Minipig Following a Single TopicalAdministration (1 g of Formulation/44 cm²) Epidermis Upper Dermis Animal(0-100 μm) (100-500 μm) Formulation ID C_(max) (μg/g) T_(max) (hr)C_(max) (μg/g) T_(max) (hr) 1% cream S0001 9.4 48 1.37 72 formulation 11% gel S0101 21.8 8 1.67 8 formulation 1

Example 18: Estimation of Human Plasma Concentration Following TopicalAdministration

The human plasma concentration at steady state (C_(ss,human)) followingtopical application of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diolwas predicted by assuming that the topically applied drug is absorbedthrough the skin at a constant rate, and

$C_{{ss},{human}} = {\frac{{Topical}{Skin}{Flux} \times {Dosing}{Area}}{{CL}_{human}}.}$

The plasma clearance (CL_(human)) was estimated from the in vitro andpreclinical pharmacokinetic studies. Using allometric scaling, based onin vivo clearance in rat and minipig, liver blood flow rate method, andIVIVE approach with well-stirred model (assuming that hepatic metabolicclearance is the major elimination pathway), CL_(human) was predicted tobe between 6 to 25 mL/min/kg. The lowest predicted clearance (6mL/min/kg predicted from allometric scaling with plasma protein bindingcorrection) was selected to evaluate the potential systemic safety riskof 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in human.

In the in vitro human skin penetration evaluation of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol loaded at 0.1% creamformulation 1, 0.5% cream formulation 1 and 1% cream formulation 1, thereceiving fluid levels were below the lower limit of quantification(LLOQ; 80 pg/mL) over 16 hours, therefore preventing the calculation ofthe skin flux values. An estimated skin flux prediction was conducted,assuming a 2-hour lag time and receiving fluid levels obtained every twohours at the LLOQ level for 16 hours, leading to a calculated flux of0.048 ng/cm²/h.

Healthy skin is an effective protective barrier to most xenobiotics;therefore the relevance of a flux value derived from the ex vivo skinpenetration assay, which uses healthy human skin from abdominoplastysurgeries, may not translate to what is observed following applicationonto unhealthy skin. In order to account for damaged skin barrier, a10-fold increase in flux was incorporated in the initial prediction ofhuman systemic exposure following topical administration of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol. Calculation of humansystemic exposure with a 100-fold increase in flux has also beenperformed to account for the worst case estimation. A 10% body surfacearea (1800 cm²) in human was used for this estimation. Therefore, forthe purpose of safety margin estimation and considering the conditionsexplained herein, the estimated C_(ss,human) is 0.34 ng/mL with thecorresponding AUC_(ss,24h) is 8.2 ng*h/mL. In clinical practice, topicaltreatment for atopical dermatitis can be up to 50% BSA (9000 cm2) andtherefore corresponding estimated C_(ss,human) and AUC_(ss,24h) with10-fold increase in flux is 0.17 ng/mL and 4.1 ng*h/mL. Differentsimulated scenarios are summarized in Table 17.

TABLE 17 Estimated Human Plasma Concentration at Steady State(Css,human) and Corresponding Area Under the Curve over 24 Hours(AUC_(24h)) Following Topical Application of 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (1% Cream Formulation 1) Topical DoseBody Estimated Estimated Skin Flux Area Clearance Weight C_(ss)AUC_(24h) (ng/cm²/h) (cm²) (ml/min/kg) (kg) (ng/mL) (ng * hr/mL) 0.0481800 6 70 0.003 0.08 (calculated) 0.48 (10-fold 1800 6 70 0.034 0.82increase) 4.8 (100-fold 1800 6 70 0.343 8.23 increase) 0.048 9000 6 700.015 0.36 (calculated) 0.48 (10-fold 9000 6 70 0.170 4.08 increase) 4.8(100-fold 9000 6 70 1.715 41.2  increase)

Example 19: Integration of Preclinical Target Engagement Studies forHuman Dose Selection

Based on the combination of data from in vitro potency, ex vivo humanskin target engagement and penetration, and minipig skin PK data, it isexpected that the 1% cream formulation 1 following daily dosing willresult in sufficient concentrations of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol at the target skin site(viable epidermis and upper dermis), resulting in AhR target engagement.

The free drug concentrations in the skin, obtained after topicalapplication of the 1% cream formulation 1 and calculated from the exvivo human skin and minipig skin PK studies (via MALDI-IMS analysis),suggest sufficient coverage of the effective concentration obtained viain vitro potency assays (50% of AhR activation in fluorescence-basedreporter assay for CYP1A1 gene expression and 50% of IL-17A productioninhibition in primary human peripheral blood CD4+ T-cells) shown inTable 18. These calculations assumed same skin binding between human andminipig and 100% dermal bioavailability after correction for unboundskin fraction.

TABLE 18 Calculated free skin concentrations (μM) of2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in the Epidermis andUpper Dermis Compartments (± SEM) as Determined by MALDI-IMS AnalysisMALDI-IMS of ex vivo human skin (n = *) MALDI-IMS of in vivo minipigskin Epidermis Upper Dermis C_(max) (n = 3 for one animal) ConcentrationConcentration Epidermis Upper Dermis at 24 h at 24 h C_(max) C_(max)Dose (0-100 μm) (100-500 μm) Dose (0-100 μm) (100-500 μm) Formulation(mg/cm²) Total Free Total Free (mg/cm²) Total Free Total Free 1% cream0.1 (non- 1448.2 ± 742.9 ± 28.3 ± 9.7 ± 0.6 0.23 (semi- 33.8 ± 17.3 ±4.9 ± 1.7 ± 0.2 form. 1 occluded) 13.6 7.0 1.7 (613-fold occluded) 4.92.5 0.5 (108-fold over AhR over AhR EC₅₀; 69-fold EC₅₀; 12-fold overIL17A over IL17A IC₅₀) IC₅₀) Note: AhR activation in fluorescence-basedreporter assay for CYP1A1 gene expression EC₅₀ = 0.0158 μM; IL-17Ainhibition in primary human peripheral blood CD4+ T-cells IC₅₀ = 0.14μM. Values reported for the MALDI-IMS analysis of ex vivo human skin arethe average of 6 skin sections, taken from 2 skin penetration replicates(3 sections per skin replicate), using 1 skin donor

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore, the Examples herein are tobe construed as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

What is claimed is:
 1. A process for preparing a compound of Formula 8

comprising: a) coupling a compound of Formula 6

or a pharmaceutically acceptable salt, solvate or hydrate thereof withthe compound of Formula 5

or a pharmaceutically acceptable salt, solvate or hydrate thereof toform a compound of Formula 7

or a pharmaceutically acceptable salt, solvate or hydrate thereof; andb) demethylating the compound of Formula 7 to form the compound ofFormula 8 or a pharmaceutically acceptable salt, solvate or hydratethereof.
 2. The process of claim 1 wherein compound 6 or apharmaceutically acceptable salt, solvate or hydrate thereof, isprepared by treating isoquinoline-3-ol with a triflating agent.
 3. Theprocess of claim 1 wherein compound 5 or a pharmaceutically acceptablesalt, solvate or hydrate thereof, is prepared by a process comprising:a) alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptablesalt, solvate or hydrate thereof, to form a compound of Formula 2

or a pharmaceutically acceptable salt, solvate or hydrate thereof; b)treating the ketone of Formula 2 or a pharmaceutically acceptable salt,solvate or hydrate thereof with a Grignard reagent, followed byelimination of water under acidic conditions to form a compound ofFormula 3

or a pharmaceutically acceptable salt, solvate or hydrate thereof; c)hydrogenating the compound of Formula 3 or a pharmaceutically acceptablesalt, solvate or hydrate thereof to form a compound of Formula 4

or a pharmaceutically acceptable salt, solvate or hydrate thereof; andd) borylating the compound of Formula 4 or a pharmaceutically acceptablesalt, solvate or hydrate thereof to form the compound of Formula 5 or apharmaceutically acceptable salt, solvate or hydrate thereof.
 4. Theprocess of claim 1 wherein the demethylation comprises a) treating thecompound of Formula 7 with boron tribromide to form the compound ofFormula 7-1

and b) hydrogenating the compound of Formula 7-1 to form the compound ofFormula
 8. 5. The process of claim 1, further comprising purifying thecompound of Formula
 8. 6. The process of claim 5 wherein the purifyingcomprises crystallization.
 7. A process for preparing a compound ofFormula 8

or a pharmaceutically acceptable salt, solvate or hydrate thereof,comprising: a) preparing a compound of Formula 5

or a pharmaceutically acceptable salt, solvate or hydrate thereof,comprising 1) alkylating 2,6-dihydroxyacetophenone or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, to form a compound ofFormula 2

 or a pharmaceutically acceptable salt, solvate or hydrate thereof; 2)treating the ketone of Formula 2 or a pharmaceutically acceptable salt,solvate or hydrate thereof with a Grignard reagent, followed byelimination of water under acidic conditions to form a compound ofFormula 3

 or a pharmaceutically acceptable salt, solvate or hydrate thereof; 3)hydrogenating the compound of Formula 3 or a pharmaceutically acceptablesalt, solvate or hydrate thereof to form a compound of Formula 4

 or a pharmaceutically acceptable salt, solvate or hydrate thereof; and4) borylating the compound of Formula 4 or a pharmaceutically acceptablesalt, solvate or hydrate thereof to form the compound of Formula 5 or apharmaceutically acceptable salt, solvate or hydrate thereof; b)preparing a compound of Formula 6

or a pharmaceutically acceptable salt, solvate or hydrate thereofcomprising treating isoquinoline-3-ol with a triflating agent; and c)coupling the compound of Formula 6 or a pharmaceutically acceptablesalt, solvate or hydrate thereof with the compound of Formula 5 or apharmaceutically acceptable salt, solvate or hydrate thereof to form acompound of Formula 7

or a pharmaceutically acceptable salt, solvate or hydrate thereof; andd) demethylating the compound of Formula 7 to form the compound ofFormula 8 or a pharmaceutically acceptable salt, solvate or hydratethereof; wherein steps a) and b) can be done in either order orsimultaneously in different reaction vessels.
 8. The process of claim 7,further comprising purifying the compound of Formula
 8. 9. The processof claim 8 wherein the purifying comprises crystallization.
 10. Aprocess for preparing compound of Formula 8

or a pharmaceutically acceptable salt, solvate or hydrate thereof,comprising demethylating a compound of Formula 7

or a pharmaceutically acceptable salt, solvate or hydrate thereof. 11.The process of claim 10 further comprising coupling a compound ofFormula 6

or a pharmaceutically acceptable salt, solvate or hydrate thereof with acompound of Formula 5

or a pharmaceutically acceptable salt, solvate or hydrate thereof toform the compound of Formula
 7. 12. The process of claim 11 furthercomprising borylating a compound of Formula 4

or a pharmaceutically acceptable salt, solvate or hydrate thereof toform the compound of Formula
 5. 13. The process of claim 12 furthercomprising hydrogenating a compound of Formula 3

or a pharmaceutically acceptable salt, solvate or hydrate thereof toform the compound of Formula
 4. 14. The process of claim 13 furthercomprising treating a ketone of Formula 2

or a pharmaceutically acceptable salt, solvate or hydrate thereof with aGrignard reagent, followed by elimination of water under acidicconditions to form the compound of Formula
 3. 15. The process of claim14 further comprising alkylating 2,6-dihydroxyacetophenone or apharmaceutically acceptable salt, solvate or hydrate thereof, to formthe compound of Formula
 2. 16. The process of claim 10 wherein thedemethylation comprises treating the compound of Formula 7 with borontribromide.
 17. The process of claim 10, further comprising purifyingthe compound of Formula
 8. 18. The process of claim 17 wherein thepurifying comprises crystallization.